Inhalable compositions for use in the treatment of pulmonary diseases

ABSTRACT

The present disclosure relates to a pharmaceutical composition comprising an inhalable immunosuppressive macrocyclic active ingredient for use in the prevention or treatment of a pulmonary disease or condition in a subject, wherein the pharmaceutical composition is administered to the subject by inhalation in form of an aerosol, and wherein the aerosol is generated by nebulization of the pharmaceutical composition using a nebulizer (100), the nebulizer comprising: a) an aerosol generator (101) comprising: a fluid reservoir (103) for holding the pharmaceutical composition or an interface configured to connect a fluid reservoir, and a vibratable membrane (110) having a plurality of apertures, the apertures being adapted to produce an aerosol comprising droplets having a mass median aerodynamic diameter (MMAD) of up to about 4.0 gm as measured with a 0.9% (w/v) aqueous solution of sodium chloride; b) a chamber (105) for temporarily accommodating the aerosol generated by the aerosol generator (101), the chamber having an inner lumen with a volume in the range of from about 50 to about 150 ml; and c) a mouthpiece (40) for delivering the aerosol supplied by the nebulizer (100) to the subject, the mouthpiece having an exhalation filter (30).

TECHNICAL FIELD

The present invention relates to pharmaceutical compositions comprisingan inhalable immunosuppressive macrocyclic active ingredient for use inthe prevention or treatment of a pulmonary disease or condition in asubject. The pharmaceutical compositions of the present invention can beadministered by inhalation of an aerosol generated with a nebulizercomprising a vibratable membrane as well as a mixing chamber.

BACKGROUND

WO 2007/065588 A1 discloses liquid pharmaceutical compositionscomprising a therapeutically effective dose of a cyclosporin, an aqueouscarrier liquid, a first solubilizing substance selected among the groupof phospholipids, and a second solubilizing substance selected among thegroup of non-ionic surfactants, i.a. suitable for pulmonary applicationin the form of an aerosol.

Pharmaceutical compositions as described above may be inhaled by asubject in need thereof. It should be noted that the cyclosporines, suchas cyclosporine A, just as many other macrocyclic immunosuppressivecompounds are very potent medications for the suppression of an immuneresponse in a patient in need of such a treatment. In other individualswhich do not need or undergo an immunosuppressive treatment, however,these potent compounds can have unwanted if not dangerous effects uponexposure.

In cases in which an immunosuppressive or other potent medication is tobe administered by inhalation, usually a nebulizer is necessary toprovide for the corresponding aerosol comprising such medication, oftenin form of an aerosol. In use of such nebulizers, however, somenebulized liquid will be discharged from the nebulizer during exhalationby the user. In particular, known nebulizers of this type comprise anambient opening and an exhalation opening each comprising a one-wayvalve allowing that ambient air is drawn into the nebulizer duringinhalation and allowing air to escape the nebulizer during exhalation. Anebulizer of this type is, for example, disclosed in EP 1 927 373 B1.

In some instances, as mentioned above, the liquid to benebulized/aerosolized may contain compounds which are detrimental forindividuals staying in the environment in which the patient inhales eventhough they serve a therapeutic purpose with respect to the disease ofthe patient. It is known in the art to use exhalation filters so as toavoid those components from being discharged (exhausted) into theenvironment. One example showing such an exhalation filter is EP 1 868570 B1.

Furthermore, especially in view of the above-described problem and inview of the fact that a macrocyclic immunosuppressant such ascyclosporine A should be administered in the minimal amount possible andexclusively or predominantly to the targeted tissues, there is stillneed for a pharmaceutical composition comprising an macrocyclicimmunosuppressant for inhalation purposes that allows for an effectivedelivery of the chosen immunosuppressive wherein as much as possible ofthe administered immunosuppressive is actually delivered to the targetedtissues and a minimized amount of the compound to be administered isexhaled by the patient during administration. Furthermore, there isstill a need for an improved transport of macrocyclic immunosuppressantsespecially to the peripheral tissues of the lungs.

It is therefore an object of the present invention to provide for apharmaceutical composition comprising a macrocyclic immunosuppressantuseful for the treatment or prevention of a pulmonary disease orcondition in a subject in need thereof that can be administered byinhalation whereby

-   -   the immunosuppressant is administered in a form that allows for        the delivery of the maximum amount or fraction actually        delivered to the target tissue; and    -   the amount or fraction of the administered immunosuppressant        that is not delivered to the target tissue and exhaled by the        subject is minimized.

Further objects of the present invention will become apparent from thepresent disclosure including the examples and claims.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a pharmaceuticalcomposition comprising an inhalable immunosuppressive macrocyclic activeingredient for use in the prevention or treatment of a pulmonary diseaseor condition in a subject,

-   -   wherein the pharmaceutical composition is administered to the        subject by inhalation in form of an aerosol, and    -   wherein the aerosol is generated by nebulization of the        pharmaceutical composition using a nebulizer (100), the        nebulizer comprising:        -   a) an aerosol generator (101) comprising:            -   a fluid reservoir (103) for holding the pharmaceutical                composition or an interface configured to connect a                fluid reservoir, and            -   a vibratable membrane (110) having a plurality of                apertures, the apertures being adapted to produce an                aerosol comprising droplets having a mass median                aerodynamic diameter (MMAD) of up to about 4.0 μm as                measured with a 0.9% (w/v) aqueous solution of sodium                chloride;        -   b) a chamber (105) for temporarily accommodating the aerosol            generated by the aerosol generator (101), the chamber having            an inner lumen with a volume in the range of from about 50            to about 150 ml; and        -   c) a mouthpiece (40) for delivering the aerosol supplied by            the nebulizer (100) to the subject, the mouthpiece having an            exhalation filter (30).

In a second aspect, the present invention provides for a method forpreventing or treating a pulmonary disease or condition in a subject,the method comprising the step of administering an inhalableimmunosuppressive macrocyclic active ingredient to said subject byinhalation in form of an aerosol comprising the immunosuppressivemacrocyclic active ingredient, preferably in liposomally solubilizedform,

-   -   wherein the aerosol is generated by nebulization of the        pharmaceutical composition using a nebulizer (100), the        nebulizer comprising:        -   a) an aerosol generator (101) comprising:            -   a fluid reservoir (103) or an interface configured to                connect a fluid reservoir, and            -   a vibratable membrane (110) having a plurality of                apertures, the apertures being adapted to produce an                aerosol comprising droplets having a mass median                aerodynamic diameter (MMAD) of up to about 4.0 μm as                measured with a 0.9% (w/v) aqueous solution of sodium                chloride;        -   b) a chamber (105) for temporarily accommodating the aerosol            generated by the aerosol generator, the chamber having an            inner lumen with a volume in the range of from about 50 to            about 150 ml; and        -   c) a mouthpiece (40) for delivering the aerosol supplied by            the nebulizer (100) to the subject, the mouthpiece having an            exhalation filter (30).            In a third aspect, the present invention provides for a kit            comprising    -   a pharmaceutical composition comprising an inhalable        immunosuppressive macrocyclic active ingredient for use in the        prevention or treatment of a pulmonary disease or condition in a        subject; and    -   a nebulizer (100), the nebulizer comprising:        -   a) an aerosol generator (101) comprising:            -   a fluid reservoir (103) for holding the pharmaceutical                composition or an interface configured to connect a                fluid reservoir, and            -   a vibratable membrane (110) having a plurality of                apertures, the apertures being adapted to produce an                aerosol comprising droplets having a mass median                aerodynamic diameter (MMAD) of up to about 4.0 μm as                measured with a 0.9% (w/v) aqueous solution of sodium                chloride;        -   b) a chamber (105) for temporarily accommodating the aerosol            generated by the aerosol generator (101), the chamber having            an inner lumen with a volume in the range of from about 50            to about 150 ml; and        -   c) a mouthpiece (40) for delivering the aerosol supplied by            the nebulizer (100) to the subject, the mouthpiece having an            exhalation filter (30).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a perspective view of a nebulizer useful for theadministration of the inhalable immunosuppressive macrocyclic activeingredient according to the present invention with an exhalation filterattached to the nebulizer via a T-shaped adapter, wherein the filter isdirected to the right in front view and a separate mouthpiece isconnected to the adapter;

FIG. 2 shows a perspective front view on the nebulizer of FIG. 1, butwith the filter being tilted to the right;

FIG. 3 shows a perspective side view of a mouthpiece for the nebulizeraccording to FIG. 1;

FIG. 4 shows an exploded view of the mouthpiece of FIG. 3 and anebulizer mixing chamber;

FIG. 5 shows a longitudinal sectional view of the nebulizer and themouthpiece of FIGS. 3 and 4.

DETAILED DESCRIPTION OF THE INVENTION

The terms “consist of”, “consists of” and “consisting of” as used hereinare so-called closed language meaning that only the mentioned componentsare present. The terms “comprise”, “comprises” and “comprising” as usedherein are so-called open language, meaning that one or more furthercomponents may or may not also be present.

The term “active ingredient” or “active pharmaceutical ingredient” (alsoreferred to as “API” throughout this document) refers to any type ofpharmaceutically active compound or derivative that is useful in theprevention, diagnosis, stabilization, treatment, or—generallyspeaking—management of a condition, disorder or disease.

The term “therapeutically effective amount” as used herein refers to adose, concentration or strength which is useful for producing a desiredpharmacological effect. In the context of the present invention, theterm “therapeutically effective” also includes prophylactic activity.The therapeutic dose is to be defined depending on the individual caseof application. Depending on the nature and severity of the disease,route of application as well as height and state of the patient, atherapeutic dose is to be determined in a way known to the skilledperson.

In the context of the present invention, a “pharmaceutical composition”is a preparation of at least one API and at least one adjuvant, which,in the simplest case, can be, for example, an aqueous liquid carriersuch as water or saline.

‘A’ or ‘an’ does not exclude a plurality; i.e. the singular forms ‘a’,‘an’ and ‘the’ should be understood as to include plural referentsunless the context clearly indicates or requires otherwise. In otherwords, all references to singular characteristics or limitations of thepresent disclosure shall include the corresponding plural characteristicor limitation, and vice versa, unless explicitly specified otherwise orclearly implied to the contrary by the context in which the reference ismade. The terms ‘a’, ‘an’ and ‘the’ hence have the same meaning as ‘atleast one’ or as ‘one or more’ unless defined otherwise. For example,reference to ‘an ingredient’ includes mixtures of ingredients, and thelike.

When used herein, the term ‘about’ or ‘ca.’ will compensate forvariability allowed for in the pharmaceutical industry and inherent inpharmaceutical products, such as differences in content due tomanufacturing variation and/or time-induced product degradation. Theterm allows for any variation, which in the practice of pharmaceuticalswould allow the product being evaluated to be considered bioequivalentin a mammal to the recited strength of a claimed product.

‘Essentially’, ‘about’, ‘approximately’, ‘substantially” and the like inconnection with an attribute or value include the exact attribute or theprecise value, as well as any attribute or value typically considered tofall within a normal range or variability accepted in the technicalfield concerned. For example, ‘substantially free of water” means thatno water is deliberately included in a formulation, but does not excludethe presence of residual moisture.

In the context of the present invention, a “colloidal aqueous solution”preferably means a solution without organic solvent consisting of mainlyunilamellar liposomes having a mean diameter of at most 100 nm and/or apolydispersity index (PI) of not more than 0.50 in which the activeagent is, at least predominantly, dissolved. Preferably, water, or morespecifically saline is the only liquid solvent contained in thepreparation. Furthermore, it is preferred that the preparation is anaqueous solution or an aqueous colloidal solution, i.e., a monophasicliquid system. Such a system is essentially free of dispersed particleshaving a greater than colloidal particle size. By convention, particlesbelow about 1 μm are regarded as colloidal particles which do notconstitute a separate phase and do not result in a physical phaseboundary. Sometimes, particles in a size range just above 1 μm are alsostill considered colloidal. Preferably, however, colloidal aqueoussolutions as used herein are essentially free of particles which doclearly not belong to the colloidal spectrum, i.e., for example,particles having a diameter of 1 μm or more.

In a first aspect, the present invention provides a pharmaceuticalcomposition comprising an inhalable immunosuppressive macrocyclic activeingredient for use in the prevention or treatment of a pulmonary diseaseor condition in a subject, wherein the pharmaceutical composition isadministered to the subject by inhalation in form of an aerosol, andwherein the aerosol is generated by nebulization of the pharmaceuticalcomposition using a nebulizer (100), the nebulizer comprising:

-   -   a) an aerosol generator (101) comprising:        -   a fluid reservoir (103) for holding the pharmaceutical            composition or an interface configured to connect a fluid            reservoir, and        -   a vibratable membrane (110) having a plurality of apertures,            the apertures being adapted to produce an aerosol comprising            droplets having a mass median aerodynamic diameter (MMAD) of            up to about 4.0 μm as measured with a 0.9% (w/v) aqueous            solution of sodium chloride;            -   b) a chamber (105) for temporarily accommodating the                aerosol generated by the aerosol generator (101), the                chamber having an inner lumen with a volume in the range                of from about 50 to about 150 ml; and            -   c) a mouthpiece (40) for delivering the aerosol supplied                by the nebulizer (100) to the subject, the mouthpiece                having an exhalation filter (30).

The pharmaceutical compositions for use according to the presentinvention comprising an inhalable immunosuppressive macrocyclic activeingredient are useful in the prevention or treatment of a broad varietyof pulmonary diseases or conditions in a subject. The term ‘subject’ asused herein means a mammal, more specifically a human, being diagnosedwith such pulmonary diseases or conditions or being threatened todevelop such diseases or conditions. In specific embodiments, term‘subject’ as used herein means a human or patient being diagnosed with apulmonary disease or condition and in need of a treatment thereof.

In specific embodiments, the pulmonary disease or condition to betreated by administration of the compositions for use according to thepresent invention is selected from the group consisting of the pulmonarydiseases asthma, refractory asthma, chronic obstructive bronchitis,parenchymal, fibrotic and interstitial lung diseases and inflammations,bronchiolitis obliterans (BOS), and acute and chronic organ transplantrejection reactions after lung transplantations and the diseasesresulting therefrom. In further specific embodiments, the pulmonarydisease or condition is bronchiolitis obliterans (BOS), optionally afteracute and chronic organ transplant rejection reactions after lungtransplantation or after hematopoietic stem cell transplantation (HSCT).

In further specific embodiments, the pharmaceutical composition for useaccording to the present invention are useful for the treatment of apulmonary disease or condition or for the prevention or delay ofprogression of such pulmonary disease or condition as described above,for example BOS, in a subject or patient being diagnosed with suchdisease or condition, specifically with BOS. The existence of BOS, forexample, can be determined on the basis of spirometric measurements ofthe forced expiratory volume (FEV). Preferably, the reduction of theforced expiratory volume in one second (FEV₁) is used as an indicator ofthe existence of BOS and, accordingly, for the risk of pulmonary chronicgraft rejection. FEV₁ measurements can be performed according to currentAmerican Thoracic Society (ATS)/European Respiratory Society (ERS)spirometry guidelines. The forced expiratory volume in one second (FEV₁)is expressed in litre (L).

Bronchiolitis obliterans (BOS) can be graded according to the degree ofprogression of this pulmonary disease as described in Estenne M, et al.Bronchiolitis obliterans syndrome 2001: an update of the diagnosticcriteria. J Heart Lung Transplant 2002; 21(3): 297-310. Based on thepercentage of decrease of the forced expiratory volume in one second(FEV₁), BOS can be graded as follows:

-   -   BOS 0: FEV₁>90% of baseline    -   BOS 0-p: FEV₁ 81% to 90% of baseline    -   BOS 1: FEV₁ 66% to 80% of baseline    -   BOS 2: FEV₁ 51% to 65% of baseline    -   BOS 3: FEV₁ 50% or less of baseline

The compositions for use according to the present invention may beparticularly useful in the treatment or for the prevention or delay ofthe progression of BOS grade I (BOS 1) or higher, more specifically ofBOS grade I or II or even more specifically BOS grade I (BOS 1).

The pharmaceutical compositions for use according to the presentinvention, in specific embodiments, may be liquid compositions. In theseembodiments, the compositions for use according to the present inventioncomprise an inhalable immunosuppressive macrocyclic active ingredientand a liquid carrier or vehicle in which the active ingredient can bedissolved, dispersed or suspended. Accordingly, in specific embodiments,the pharmaceutical composition for use according to the presentinvention is a liquid composition comprising an aqueous liquid vehicle.In further specific embodiments, the liquid vehicle is an aqueous liquidvehicle which may comprise water and optionally one or morephysiologically acceptable organic solvents, such as ethanol orpropylene glycol or others, preferably, however, ethanol and/orpropylene glycol. In further specific embodiments, the liquid vehiclecomprises one or more pharmaceutically acceptable salts such as sodiumchloride (NaCl). Accordingly, the liquid vehicle may comprise saline ormay essentially consist of saline. In these specific embodiments as wellas in other embodiments, in which the aqueous liquid vehicle comprisesfurther constituents or solvents, the concentration of sodium chloridecan range from about 0.1 to about 7% (w/v) or from about 0.1 to about 3%(w/v) or from about 0.1 to about 0.9% (w/v). Preferably, a salinesolution with a sodium chloride concentration of about 0.25% (w/v) isused, wherein the term “w/v” means the weight of the dissolved sodiumchloride per volume of the liquid vehicle comprised by the aqueousliquid composition.

The pharmaceutical compositions for use according to the presentinvention further comprise an inhalable macrocyclic immunosuppressiveactive ingredient. Examples of such inhalable macrocyclicimmunosuppressive active ingredients comprise, but are not limited tocyclosporine A (CsA), tacrolimus, sirolimus and/or everolimus,preferably in a therapeutically effective amount. An immunosuppressivecompound as named above may be present as the only active ingredient orin form of a mixture of two or more different inhalableimmunosuppressive macrocyclic active ingredients, optionally incombination with other non-immunosuppressive and/or non-macrocyclicactive ingredients. In specific embodiments, however, the pharmaceuticalcompositions for use according to the present invention comprise justone inhalable immunosuppressive macrocyclic active ingredient.

In preferred embodiments, however, the inhalable immunosuppressivemacrocyclic active ingredient is selected from cyclosporine A (CsA) andtacrolimus. In further preferred embodiments, the inhalableimmunosuppressive active ingredient comprised by the presentpharmaceutical compositions for use is cyclosporine A (ciclosporin A;CsA(cyclo-[[(E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoyl]-L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]). Pharmaceutical compositionscomprising CsA or more specifically L-CsA are known e.g. from US2009169607 A1 and can be prepared accordingly.

In other embodiments, however, the inhalable macrocyclicimmunosuppressive active ingredient comprised by the presentpharmaceutical compositions for use is tacrolimus.

It should be noted that the inhalable macrocyclic immunosuppressants asdescribed above, especially cyclosporine A (CsA) and tacrolimus are verypotent active compounds which show immunomodulating effects in a patientor other individual when exposed to very low amounts or concentrationsof these compounds. As already noted above, however, this may bedetrimental or even hazardous for individuals staying in the environmentin which the patient inhales even though they serve a therapeuticpurpose with respect to the disease of the patient. On this basis, it isespecially important to provide for nebulizer or mouthpiece that allowsfor the effective administration of aerosols comprising such compoundsto a patient while minimizing the risk for unwanted exposures ofindividuals other than the patient by exhalation of these compounds, ormore specifically, the portion of these active ingredients which havenot been absorbed by the patient during inhalation.

In specific embodiments, the pharmaceutical composition for useaccording to the present invention, more specifically the liquidpharmaceutical compositions for use according to the present inventioncomprise the selected immunosuppressive macrocyclic active ingredient,especially cyclosporine A (CsA) or tacrolimus, preferably cyclosporine A(CsA) in a concentration in the range of from about 1 mg/mL to about 10mg/mL, preferably from about 2 mg/mL to about 8 mg/mL, more preferablyfrom 2.5 mg/mL to about 6 mg/mL, even more preferably from 3 mg/mL toabout 4 mg/mL, especially at a concentration of about 4 mg/mL.

In further specific embodiments, in the pharmaceutical compositions foruse according to the present invention, the inhalable immunosuppressiveactive ingredient, especially cyclosporine A, is present in liposomallysolubilized form (L-CsA). In such cases in which liquid, preferablyaqueous liquid pharmaceutical compositions for use according to thepresent invention comprise cyclosporine A in liposomally solubilizedform (L-CsA), the corresponding concentration of L-CsA may be in therange of from about 3 mg/mL to about 5 mg/mL, more specifically in therange of from about 3.8 mg/mL to about 4.2 mg/mL.

In further specific embodiments, especially in which the presentpharmaceutical compositions for use comprise the inhalableimmunosuppressive macrocyclic active ingredient in liposomallysolubilized form, the pharmaceutical composition in liquid form may beobtained by reconstitution of a lyophilisate comprising theimmunosuppressive macrocyclic active ingredient and liposome formingstructures.

Such liposome forming structures may further comprise a membrane-formingsubstance selected from the group of phospholipids or two or moredifferent membrane-forming substances selected from the group ofphospholipids. The term “membrane-forming substance” as used hereinmeans that the substance is capable of forming a lipid bilayer membraneby self-assembly in an aqueous carrier liquid, such as water or salineand/or is capable of forming liposomes in an aqueous carrier liquidunder circumstances as described in further detail below.

The liposome-forming structures that may be comprised by the presentpharmaceutical compositions may comprise a bilayer membrane formed ofthe membrane-forming substance selected from the group of phospholipids.The liposome-forming structures may or may not have a continuous orclosed bilayer membrane. In specific embodiments, the liposome-formingstructures are at least partly present in unilamellar form or,preferably, are predominantly present in unilamellar form. The term“unilamellar” as used herein means that the correspondingliposome-forming structures only comprise a single layer formed by asingle lipid bilayer membrane and not a plurality of lipid bilayermembranes in a layered arrangement.

In specific embodiments, the inhalable macrocyclic immunosuppressiveingredient, specifically CsA that may be comprised by liposome-formingstructures as described above is at least partially incorporated (orintercalated) in the bilayer membrane of the liposome-formingstructures. The term “incorporated” as used herein means, with regard toCsA being a lipophilic compound, that CsA is located or intercalated inthe inner lipophilic part of the bilayer lipid membrane rather than onthe hydrophilic outer surfaces of the lipid bilayer membrane (whereasthe terms surfaces can mean both surfaces, or more specifically theinner or outer surface of the bilayer membrane forming theliposome-forming structures). In further embodiments, the inhalableimmunosuppressive macrocyclic active ingredient, specifically CsA orL-CsA is predominantly (for example by at least about 90% or even atleast about 95% to about 97.5%) incorporated in the bilayer membrane ofthe liposome-forming structures.

Phospholipids that may be comprised by the liposome forming structuresof the present invention are, in particular, mixtures of natural orenriched phospholipids, for example, lecithins such as the commerciallyavailable Phospholipon® G90, 100, or Lipoid 90, S 100.

Phospholipids are amphiphilic lipids which contain phosphorus. Knownalso as phosphatides, they play an important role in nature, especiallyas the double layer forming constituents of biological membranes andfrequently used for pharmaceutical purposes are those phospholipidswhich are chemically derived from phosphatidic acid. The latter is a(usually doubly) acylated glycerol-3-phosphate in which the fatty acidresidues may be of different lengths. The derivatives of phosphatidicacids are, for example, the phosphocholines or phosphatidylcholines, inwhich the phosphate group is additionally esterified with choline, aswell as phosphatidylethanolamine, phosphatidylinositols etc. Lecithinsare natural mixtures of various phospholipids which usually contain ahigh proportion of phosphatidylcholines. Preferred phospholipidsaccording to the invention are lecithins as well as pure or enrichedphosphatidylcholines such as dimyristoylphospatidylcholine,di-palmitoyl-phosphatidylcholine and distearoylphosphatidylcholine.Accordingly, in preferred embodiments, the membrane-forming substanceselected from the group of phospholipids is a mixture of naturalphospholipids.

In preferred embodiments, the membrane-forming substance selected fromthe group of phospholipids is a lecithin containing unsaturated fattyacid residues. In yet further preferred embodiments, themembrane-forming substance selected from the group of phospholipids is alecithin selected from the group consisting of soy bean lecithin, LipoidS100, Phospholipon® G90, 100 or a comparable lecithin. In furtherpreferred embodiments, the membrane-forming substance selected from thegroup of phospholipids is selected from Lipoid S100, Lipoid S75,particularly Lipoid S100.

The pharmaceutical compositions for use according the present inventionor, more specifically, the liposome-forming structures that may becomprised by the present pharmaceutical compositions may furthercomprise a solubility-enhancing substance or two or more differentsolubility-enhancing substances selected from the group of non-ionicsurfactants. Non-ionic surfactants have—as other surfactants—at leastone rather hydrophilic and at least one rather lipophilic molecularregion. There are monomeric, low molecular weight non-ionic surfactantsand non-ionic surfactants having an oligomeric or polymeric structure.Examples of suitable non-ionic surfactants suitable assolubility-enhancing substances of the liposome-forming structures asdescribed above comprise polyoxyethylene alkyl ethers, polyoxyethylenesorbitan fatty acid esters such as, for example, polyoxyethylenesorbitan oleate, sorbitan fatty acid esters, poloxamers, vitamin E-TPGS(D-a-tocopheryl polyethylene glycol 1000 succinate) and tyloxapol.

In specific embodiments, the solubility-enhancing substance selectedfrom the group of non-ionic surfactants is selected from the group ofpolysorbates and vitamin E-TPGS, preferably is selected from the groupof polysorbates. In a particularly preferred embodiment, thesolubility-enhancing substance selected from the group of non-ionicsurfactants is polysorbate 80.

In specific embodiments of the present pharmaceutical compositions, theamount of the membrane-forming substance selected from the group ofphospholipids, preferably the lecithin is larger than the amount of thesolubility-enhancing substance selected from the group of non-ionicsurfactants. In exemplary embodiments, the weight ratio of the membraneforming substance (or the sum of the membrane-forming substances)selected from the group of phospholipids, preferably the lecithin, tothe solubility enhancing substance (or the sum of the solubilityenhancing substances) selected from the group of non-ionic surfactants,preferably the polysorbate, is selected in the range of from about 15:1to about 9:1, preferably from about 14:1 to about 12:1, for example,about 13:1.

In further specific embodiments, the weight ratio between the (sum ofthe) membrane-forming substance(s) selected from the group ofphospholipids and the solubility-enhancing substance selected from thegroup of non-ionic surfactant on the one hand and the immunosuppressivemacrocyclic active ingredient, preferably CsA, on the other hand isselected in the range of from about 5:1 to about 20:1, preferably fromabout 8:1 to about 12:1 and more preferably about 10:1.

In yet further specific embodiments, the weight ratio between themembrane-forming substance selected from the group of phospholipids,preferably the lecithin, the solubility-enhancing substance selectedfrom the group of non-ionic surfactants, preferably the polysorbate andthe immunosuppressive macrocyclic active ingredient, preferably CsA, isselected in the range of from about 15:1:1.5 to about 5:0.3:0.5, andpreferably at about 9:0.7:1.

The pharmaceutical composition for use according to the presentinvention may further comprise one or more further excipients. Suitableexcipients are known to the skilled person. For example, the presentpharmaceutical compositions can optionally contain pH-correcting agentsin order to adjust the pH, such as physiologically acceptable bases,acids or salts, optionally as buffer mixtures. In this context, the term“physiologically acceptable” does not mean that one of the excipientsmust be tolerable an its own and in undiluted form, which would not bethe case, for example, for sodium hydroxide solution, but means that itmust be tolerable at the concentration in which it is contained in thelyophilized pharmaceutical composition, especially after reconstitution.

Suitable pH-correcting agents or buffers for adjusting the pH may beselected, inter alia, with regard to the intended route of application.Examples for potentially useful excipients of this group comprise sodiumhydroxide solution, basic salts of sodium, calcium or magnesium such as,for example, citrates, phosphates, acetates, tartrates, lactates etc.,amino acids, acidic salts such as hydrogen phosphates or dihydrogenphosphates, especially those of sodium, moreover, organic and inorganicacids such as, for example, hydrochloric acid, sulphuric acid,phosphoric acid, citric acid, cromoglycinic acid, acetic acid, lacticacid, tartaric acid, succinic acid, fumaric acid, lysine, methionine,acidic hydrogen phosphates of sodium or potassium etc.

In some embodiments, a liquid aqueous pharmaceutical composition for useaccording to the present invention comprises buffers to ensure a neutralor acidic pH of the pharmaceutical composition after reconstitution.Preferably, the pH of the present pharmaceutical composition is in therange of at most about 8.5 or in the range of about 2.5 to about 7.5.For pulmonary or parenteral application, a pH of about 4 to about 7.5 ispreferred, provided that this is compatible with other requirements ofthe formulation such as, for example, stability aspects. Particularlypreferred is a pharmaceutical composition which is buffered with aphosphate buffer to ensure a pH in the range of 6.0 to 7.5 or from 6.0to 7.0 or in the range of from 6.3 to 6.7, whereby the stability of thecomposition can be markedly improved and the occurrence of undesirablelysolecithin during storage can be effectively reduced.

Furthermore, the present pharmaceutical composition, especially when inform of an aqueous liquid, may or may not contain osmotically activeadjuvants in order to adjust it to a desired osmolality, which isimportant in certain applications such as especially for inhalation, inorder to achieve good tolerability. Such adjuvants are frequentlyreferred to as isotonizing agents even if their addition does notnecessarily result in an isotonic composition after reconstitution, butin an isotonicity close to physiological osmolality in order to achievethe best possible physiological tolerability.

A particularly frequently used isotonizing agent is sodium chloride. Inanother embodiment, the present pharmaceutical compositions contain anessentially neutral salt as isotonizing agent which is not sodiumchloride, but, for example, a sodium sulphate or sodium phosphate. Itshould be noted, however, that the isotonizing agent may also becomprised by the aqueous vehicle or carrier liquid as described above,for example in form of an aqueous solution of sodium chloride (saline).In this case, however, salts other than sodium salts may be alsopreferable. Thus, it is known that certain calcium and magnesium saltshave a positive or supporting effect in the inhalation of active agentsolutions, possibly because they themselves counteract the localirritations caused by the administration and because they have abronchodilatory effect which is currently postulated in the clinicalliterature (for example Hughes et al., Lancet. 2003; 361 (9375): 2114-7)and/or because they inhibit the adhesion of germs to the proteoglycansof the mucosa of the respiratory tract so that the mucociliary clearanceas the organism's natural defense against pathogens is supportedindirectly (K. W. Tsang et al., Eur. Resp. 2003. 21, 932-938).Advantageous may be, for example, magnesium sulphate, which hasexcellent pulmonary tolerability and can be inhaled without concern, aswell as calcium chloride (1-10 mmol).

In further specific embodiments, the pharmaceutical compositions for useaccording to the present invention comprise one or more furtherexcipients which are selected from buffers and chelating agents.Exemplary compounds suitable as buffers for the adjustment of the pH ofthe present pharmaceutical compositions after reconstitution comprise,for example, sodium dihydrogen phosphate dihydrate and/or disodiumhydrogen phosphate dodecahydrate, sodium hydroxide solution, basic saltsof sodium, calcium or magnesium such as, for example, citrates,phosphates, acetates, tartrates, lactates etc., amino acids, acidicsalts such as hydrogen phosphates or dihydrogen phosphates, especiallythose of sodium, moreover, organic and inorganic acids such as, forexample, hydrochloric acid, sulphuric acid, phosphoric acid, citricacid, cromoglycinic acid, acetic acid, lactic acid, tartaric acid,succinic acid, fumaric acid, lysine, methionine, acidic hydrogenphosphates of sodium or potassium etc. and further buffer systems asdescribed above. In further specific embodiments, the pharmaceuticalcompositions for use according to the present invention comprise one ormore further excipients which are selected from chelating agents,example, disodium edetate dihydrate, calcium sodium EDTA, preferablydisodium edetate dihydrate.

The pharmaceutical compositions for use according to the presentinvention may be provided in solid form such as in form of alyophilisate that is suitable for and may be reconstituted in an aqueouscarrier liquid. The term “reconstituted” as used herein means that thelyophilized pharmaceutical compositions obtained or generated by thelyophilization process in form of a solid material may be re-dissolvedor re-dispersed, preferably re-dispersed in an aqueous carrier liquid.

In specific embodiments, such lyophilized pharmaceutical compositionssuitable for the preparation of the pharmaceutical compositions for useaccording to the present invention may further comprise at least onedisaccharide selected from the group consisting of saccharose (sucrose;the terms ‘saccharose’ and ‘sucrose’ as used herein have the samemeaning and are used synonymously for β-D-fructofuranosylα-D-glucopyranoside; CAS number 57-50-1), lactose(β-D-galactopyranosyl-(1→4)-D-glucose; CAS number 63-42-3) and trehalose(α-D-glucopyranosyl-(1→1)-α-D-glucopyranoside; CAS number 99-20-7). Infurther specific embodiments, the at least one disaccharide is presentin an amount of at least about 40 wt.-% with regard to the total weightof the lyophilized composition. In some embodiments, the at least onedisaccharide is present in an amount of from at least about 40 wt.-% upto about 95 wt.-% or up to about 90 wt.-% or up to about 85 wt.-% or upto about 80 wt.-%, all with regard to the total weight of thelyophilized composition.

In further specific embodiments, the lyophilized compositions suitablefor the preparation of the pharmaceutical compositions of the presentinvention comprise saccharose and/or trehalose, preferably saccharose asthe disaccharide which is present in an amount of at least about 40wt.-% with regard to the total weight of the lyophilized composition. Inyet further embodiments, the lyophilized compositions suitable for thepreparation of the present pharmaceutical compositions by reconstitutionmay comprise the at least one disaccharide, preferably saccharose and/orlactose, especially saccharose, in an amount selected in the range offrom about 50 wt.-% to about 80 wt.-% or about 75 wt.-%, with regard toor based on the total weight of the lyophilized composition. In furtherpreferred embodiments, the lyophilized pharmaceutical compositions maycomprise the at least one disaccharide, preferably saccharose and/orlactose, especially saccharose in an amount selected in the range offrom about 60 wt.-% to about 75 wt.%, even more preferably selected inthe range of from about 65 wt.-% to about 70 wt.-% with regard to thetotal weight of the lyophilized composition.

In further specific embodiments, the lyophilized compositions comprisingan inhalable immunosuppressive macrocyclic active ingredient inliposomally solubilized form, preferably L-CsA, which are suitable forthe preparation of the present pharmaceutical compositions have beenprepared in the presence of the at least one disaccharide selected fromsaccharose, lactose and/or trehalose.

Without wishing to be bound by theory, this may be attributed to thestabilizing effect of the disaccharide selected from the group ofsaccharose, lactose and trehalose which is preferably present in anamount of at least 40 wt.-%, based on the total weight of thelyophilized pharmaceutical composition. Furthermore, the above-describedbeneficial properties of the lyophilized pharmaceutical compositions,preferably L-CsA, may be attributed to the fact that the disaccharideselected from the group consisting of saccharose, lactose and trehalose,preferably saccharose, is present on the outside as well in the innerlumen of the liposome-forming structures.

In further embodiments, the lyophilized compositions suitable for thepreparation of the present pharmaceutical compositions by reconstitutionmay comprise CsA in an amount of from about 2 to about 4 wt.-%,preferably of from about 2.2 to about 3.4 wt.-% or even more preferablyof from about 2.4 to about 3.4 wt.-% or from about 2.4 wt.-% to about3.0 wt.-%, based on the weight of the lyophilized composition. Infurther specific embodiments, in such lyophilized compositions, theratio of the weight of the at least one disaccharide to the weight ofcyclosporine A in the lyophilized composition may be selected in therange of from about 10:1 to about 30:1, or from about 20:1 to about 30:1or from about 20:1 to about 27.5:1 or even from about 22.5:1 to about27.5:1.

The lyophilized precursor compositions suitable for the preparation ofthe present pharmaceutical compositions by reconstitution may be isdissolved or, more specifically, dispersed in an aqueous carrier liquid,preferably in a sterile aqueous carrier liquid. The aqueous carrierliquid may be water or an aqueous solution of pharmaceuticallyacceptable salts or isotonizing agents and preferably may be sterile. Inpreferred embodiments, however, the sterile aqueous carrier liquid is anaqueous sodium chloride solution, preferably with the sodium chloridecontent of all 0.25% (w/v). Furthermore, the sterile aqueous carrierliquid may further comprise one or more buffer agents, preferably asdescribed above. Preferably, the sterile aqueous carrier liquid,especially the aqueous sodium chloride solution has a pH-value in therange of from 4.0 to 7.0 and an osmolality in the range of from about 60to about 100 mOsmol/kg.

Advantageously, the sterile aqueous carrier liquid is provided in anamount suitable for the preparation of pharmaceutical composition foruse according to the present invention in form of an aqueous liposomaldispersion for inhalation comprising CsA or another immunosuppressivemacrocyclic active ingredient, e.g. tacrolimus, in liposomallysolubilized form. In specific embodiments, the amounts of thelyophilized precursor composition and the aqueous carrier liquid may bechosen in the ranges as exemplarily described above. In furtherpreferred embodiments, the amount of the chosen lyophilized precursorcomposition comprising at least one disaccharide selected from the groupconsisting of saccharose, lactose and trehalose, preferably in an amountof at least 40 wt.-% with regard to the total weight of the lyophilizedcomposition, and the amount of the aqueous carrier liquid may be chosenso that the resulting liquid liposomal dispersion has a content of theat least one disaccharide selected from the group consisting ofsaccharose, lactose and trehalose, preferably saccharose, in the rangeof from about 5 to about 15 wt.-%, preferably in the range of from about7.5 to about 12.5 wt.-%, based on the total weight of the resultingpharmaceutical composition for use according to the present invention.

In particularly preferred embodiments, at least one disaccharideselected from the group consisting of saccharose, lactose and trehaloseis present in the resulting liquid liposomal dispersion in an amount inthe range of from about 5 to about 10 wt.-% or from about 7.5 to about10 wt.-%, or in an amount of about 7.5 wt.-% or about 10 wt.-%, allbased on the total weight of the liquid liposomal dispersion.

In exemplary embodiments, the sterile aqueous carrier liquid, especiallythe aqueous sodium chloride solution as described above is provided inan amount of about 2 5 1.10 mL to about 1.50 mL to be combined with analiquot of about 185 mg of a lyophilized precursor composition asdescribed in Example 1 containing about 2.7 wt.-% of CsA (correspondingto 5 mg of CsA). In further exemplary embodiments, the sterile aqueouscarrier liquid, especially the aqueous sodium chloride solution asdescribed above is provided in an amount of about 2.20 mL to about 2.80mL to be combined with an aliquot of about 375 mg of the lyophilizedprecursor composition as described in Example 1 containing about 2.7wt.-% of CsA (corresponding to 10 mg of CsA).

In specific embodiments, the pharmaceutical compositions for useaccording to the present invention may be provided in form of a liquidliposomal dispersion comprising an aqueous carrier liquid or vehicle anda therapeutically effective amount of the chosen macrocyclicimmunosuppressive active ingredient, preferably CsA, in liposomallysolubilized form. In further embodiments, the liquid liposomaldispersion is essentially free from visible particles. The liposomescomprised by said dispersion preferably may have an average diameter or,more specifically, a z-average diameter of at most about 100 nm asmeasured by photon correlation spectroscopy using a Malvern ZetaSizer.Preferably, the liquid liposomal dispersion comprises liposomes with az-average diameter as measured by photon correlation spectroscopy(Malvern ZetaSizer) in the range of from about 40 nm to about 100 nm andeven more preferably in the range of from about 40 nm to about 70 nm.Such a liquid liposomal dispersion may have a polydispersity index (PI)as measured by photon correlation spectroscopy of up to about 0.50,preferably of up to about 0.4 and even more preferably in the range offrom about 0.1 to about 0.3. Furthermore, such liquid liposomaldispersions comprising the chosen macrocyclic immunosuppressive activeingredient, preferably CsA, in liposomally solubilized form may have anosmolality in the range of from about 300 to about 550 mOsmol/kg,preferably in the range of from about 430 to about 550 mOsmol/kg. ThepH-value of such liquid liposomal dispersions preferably is in the rangeof from about 6.0 to 7.0. In further embodiments, after 1:10 dilutionthe liquid liposomal dispersion according to this aspect of theinvention has a turbidity of up to 200 NTU (Nephelometric TurbidityUnits).

In exemplary embodiments, the present pharmaceutical compositions foruse may comprise the inhalable macrocyclic active ingredient such astacrolimus or CsA, preferably CsA, in form of a liquid solution,specifically in form of an aqueous liquid solution, or, morespecifically in form of a liquid dispersion as described above. Infurther exemplary embodiments, such liquid compositions may comprisecyclosporine A (CsA) in a concentration in the range of from about 0.2to about 20 mg/mL, often in an amount from about 1 mg/mL to about 10mg/mL based on the amount of the final liquid pharmaceutical compositionto be nebulized. In case of cyclosporine A, especially in liposomallysolubilized form (L-CsA) this active ingredient often is comprised in anamount of about 2 mg/mL to about 8 mg/mL, preferably from about 2 mg/mLto about 6 mg/mL, more preferably from 2.5 mg/mL to about 6 mg/mL, evenmore preferably from 3 mg/mL to about 4 mg/mL, especially at aconcentration of about 4 mg/mL as already described above.

In many cases, the phospholipids or lecithins as described above may bepresent in the liquid pharmaceutical composition for use according tothe present invention in an amount of from about 0.2 to about 15 wt.-%or from about 1 to about 8 wt.-%, based on the total weight of the finalcomposition to be nebulized.

Furthermore, the non-ionic surfactants as described above, preferablythe polysorbates such as Tween 80 may be present in the liquidpharmaceutical compositions for use according to the present inventionin an amount of from about 0.01 to about 5 wt.-% or from about 0.1 toabout 2 wt.-%, based on the total weight of the final composition to benebulized.

The pharmaceutical composition for use according to the presentinvention is administered to the subject by inhalation in form of anaerosol as described in further detail below, whereas the aerosol isgenerated by nebulization or aerosolization of the presentpharmaceutical composition. The nebulization or aerosolization of thepresent pharmaceutical compositions, preferably of the present liquidpharmaceutical compositions is accomplished by using a nebulizer. Inpreferred embodiments, such a nebulizer is able to convert the presentpharmaceutical compositions comprising the macrocyclic immunosuppressiveactive ingredient such as CsA or tacrolimus in form of a solution,colloidal formulation or suspension, especially when provided inliposomally solubilized form as described above, into a high fraction ofdroplets which are able to reach the periphery of the lungs.

The nebulizer for the generation of the aerosol comprising thepharmaceutical composition for use according to the present inventioncomprises as a component a) an aerosol generator comprising a fluidreservoir for holding the pharmaceutical composition or an interfaceconfigured to connect a fluid reservoir, and a vibratable membranehaving a plurality of apertures, the apertures being adapted to producean aerosol comprising droplets having a mass median aerodynamic diameter(MMAD) of up to about 4.0 μm as measured with a 0.9% (w/v) aqueoussolution of sodium chloride.

The aerosol generator according to component a) of the nebulizer usefulfor the nebulization of the present pharmaceutical compositions may be aso-called membrane aerosol generator comprising a vibratable membranehaving a plurality of minute apertures in a central region as describedin further detail below. The pharmaceutical composition, specificallythe liquid pharmaceutical composition to be nebulized may be applied toone side of the membrane in the central region and the membrane isvibrated by means of a vibrator (such as a piezoelectric element)typically at a frequency in the range of from about 50 to about 300 kHz,more specifically in the range of from about 60 to about 200 kHz, orfrom about 80 to about 180 kHz or from about 100 to about 140 kHz. Dueto the vibration, the liquid pharmaceutical composition applied to oneside of the membrane passes the apertures and is nebulized on theopposite side of the membrane. Accordingly, in specific embodiments, theaerosol generator comprises a piezoelectric element (such as apiezoelectric crystal) as a vibration generator.

The vibratable membrane of the aerosol generator may have a convex shapecurving towards the aerosol release side of the membrane. In specificembodiments, the vibratable membrane separates the fluid reservoir andthe chamber. The vibratable membrane may be made of a metal such assteel or other metals or materials which are compatible with theadministration of pharmaceutical compositions such as the compositionsfor use according to the present invention. In preferred embodiments,however the vibratable membrane comprises or is made of stainless steel.

The vibratable membrane of the aerosol generator has a plurality ofapertures through which the pharmaceutical composition for use accordingto the present invention may be transported and thereby nebulized oraerosolized. The plurality of apertures are adapted to produce anaerosol comprising droplets having a mass median aerodynamic diameter(MMAD) typically in the range of below 5 μm or of up to about 4.0 μm asmeasured by nebulization of a 0.9% (w/v) aqueous sodium chloridesolution. In specific embodiments, the plurality of apertures of thevibratable membrane are adapted to produce an aerosol comprisingdroplets having a mass median aerodynamic diameter (MMAD) in the rangeof from about 1.5 μm to about 5.0 μm, such as from about 1.5 μm to about4.0 μm or from about 2.0 μm to about 4.0 μm or from 2.4 μm to about 4.0μm as measured by nebulization of a 0.9% (w/v) aqueous sodium chloridesolution.

In further specific embodiments, the plurality of apertures are adaptedto produce an aerosol comprising droplets having a mass medianaerodynamic diameter (MMAD) in the range of from about 1.5 μm to about3.9 μm, such as from 2.0 μm to about 3.9 μm or from 2.4 μm to about 3.9μm as measured by nebulization of a 0.9% (w/v) aqueous sodium chloridesolution.

In alternative embodiments, the mass median aerodynamic diameter (MMAD)of the droplets generated by the vibratable membrane comprising theplurality of apertures adapted accordingly can be determined by thenebulization or aerosolization of an aqueous solution of liposomallysolubilized CsA (L-CsA) with a CsA-concentration of 4.0 mg/mL asdescribed in Example 2.2 below. According to these embodiments, theplurality of apertures are adapted to produce an aerosol comprisingdroplets having a mass median aerodynamic diameter (MMAD) typicallybelow about 6 μm, such as in the range of from about 2.0 μm to about 5.5μm, or from 2.5 μm to about 4.5 μm or from about 2.8 μm to about 4.4 μm.

The values for the mass median aerodynamic diameter (MMAD) as referredto herein typically may be associated with a Geometric StandardDeviation (GSD) in the range of up to 2.4, more specifically of up to2.2 or of up to 2.0 or even of lower than 2.0 such as up to 1.8 or up to1.7 or, more specifically, may be associated with a Geometric StandardDeviation (GSD) in the range of 1.1 up to 2.4, more specifically of 1.2up to 2.2 or of 1.3 up to 2.0. In cases in which the GSD value is below2.0 the corresponding droplet size distribution generated by the aerosolgenerator or the vibratable membrane, respectively, is referred to as anarrow droplet size distribution or as monodisperse aerosols.

The term ‘droplets’ as used herein refers to droplets or particles ofthe aerosolized pharmaceutical composition for use according to thepresent invention comprising the chosen immunosuppressive macrocyclicactive ingredient such as CsA or tacrolimus. In context with thedetermination of the MMAD of the droplets generated by the vibratablemembrane or the plurality of apertures, respectively, the term‘droplets’ may also refer to droplets of an 0.9% (w/v) aqueous sodiumchloride solution.

The mass median aerodynamic diameter (MMAD) and other metrics of theaerosolized pharmaceutical compositions can be determined by methodsknown to those of skill in the art by means of e.g. an impactor such asa cascade impactor or by laser diffraction analysis as described e.g. inEur. Ph. 2.9.44 or to USP chapter <1601>. As a cascade impactor, amultistage cascade impactor may be used such as an ‘Anderson CascadeImpactor’ (ACI) or preferably a ‘Next Generation Impactor’ (NGI). Thesemethods allow for the determination of several metrics of the generatedaerosol comprising the present pharmaceutical compositions, such as theMMAD as mentioned above, the fine particle dose or fraction (FPD orFPF), the geometric standard deviation (GSD), as well as the respirabledose or fraction (RD or RF).

The use of a multistage cascade impactor such as the ACI or preferablythe NGI allows for the characterization of the aerodynamic metrics e.g.generated by the aerosolization/nebulization of a 0.9% (w/v) solution ofNaCl as well as for the aerosolization/nebulization of a liquidpharmaceutical composition for use according to the present invention.

The vibratable membrane useful for the nebulization or aerosolization ofthe present pharmaceutical compositions may typically comprise fromabout 1000 to about 5000 apertures, or from about 2000 to about 4000apertures, often from about 1500 to about 3500 apertures. Based on atypical perforated surface area of such a membrane with a diameter lessthan about 30 mm², preferably from about 5 mm² to about 30 mm², morepreferred from about 6 mm² to about 20 mm²and even more preferred fromabout 7 mm² to about 15 mm², the vibratable membrane typically may havefrom about 30 to about 700 apertures per mm², often from about 60 toabout 600 or from about 80 to about 500 or from about 100 to about 400apertures per mm² of the perforated surface area.

The mean geometrical diameter of the apertures as measured by scanningelectron microscopy (SEM) typically may be up to 4.0 μm or, morespecifically in the range of from about 1.5 μm to about 3.0 μm, or fromabout 1.6 μm to about 2.8 μm or from about 1.8 μm to about 2.6 μm with astandard deviation of typically +/−0.4 μm or more specifically of +/−0.3μm or even +/−0.2 μm.

In specific embodiments, the plurality of apertures of the vibratablemembrane or, more specifically, each aperture of the plurality ofapertures may have a tapered shape narrowing towards the aerosol releaseside of the vibratable membrane. Accordingly, the aperture may be formedas a channel which continuously or discontinuously narrows towards theaerosol release side of the vibratable membrane. In further specificembodiments, the apertures or a single aperture of the plurality ofapertures of the vibratable membrane, accordingly, may have an exitdiameter corresponding to the minimal mean geometrical diameter of theapertures as described above.

The aerosol generator further comprises a fluid reservoir for holdingthe pharmaceutical composition for use according to the presentinvention or an interface configured to connect a fluid reservoirholding the pharmaceutical composition for use according to the presentinvention. In specific embodiments, the aerosol generator furthercomprises a fluid reservoir for holding the pharmaceutical compositionfor use according to the present invention. Through the fluid reservoira liquid such as specifically the liquid pharmaceutical composition foruse according to the present invention may be applied to one side of thecentral region of the vibratable membrane containing the plurality ofapertures. The fluid reservoir may be closed by a lid and typically mayhave a volume of from about 1 mL to about 10 mL.

The nebulizer for the generation of the aerosol comprising thepharmaceutical composition for use according to the present inventionfurther comprises as a component b) a chamber for temporarilyaccommodating the aerosol generated by the aerosol generator, thechamber having an inner lumen with a volume in the range of from about50 to about 150 mL. In specific embodiments, the inner lumen of thechamber may have a volume of more than 60 mL and preferred more than 90mL such as in the range of from about 70 to about 130 mL or in the rangeof from about 75 to about 125 ml or more specifically in the range offrom about 80 to about 120 mL and even more specifically in the range offrom about 90 to about 110 mL or to about 100 mL.

Furthermore, the nebulizer for the generation of the aerosol comprisingthe pharmaceutical composition for use according to the presentinvention comprises as a component c) a mouthpiece for delivering theaerosol supplied by the nebulizer to the subject, the mouthpiece havingan exhalation filter.

The mouthpiece allows for delivering the pharmaceutical compositions foruse according to the present invention supplied by the nebulizer to thesubject to be treated and may be attached to the nebulizer. According toan aspect, the mouthpiece may comprise a body defining a fluid path froman inlet port connectable to the nebulizer to an inhalation opening tobe received in the mouth of the patient. Moreover, the mouthpiece alsohas an exhalation filter which may or may not be integrated into themouthpiece. In particular embodiments, the filter may have a filter basein fluid communication with the fluid path, a filter top detachablyconnected to the filter base and a filter material provided between thefilter base and the filter top. The filter top may have an exhalationopening cooperating with a one-way valve allowing exhaustion of fluidfrom the fluid path through the filter material to the outside of themouthpiece upon exhalation of a patient through the inhalation opening.In one embodiment, the one-way valve may be configured by a circulardisk made of a flexible material such as silicone or thermoplasticelastomer (TPE), covering the exhalation opening on a side opposite tothe filter material. Accordingly, in this embodiment the disk is pushedaway from the valve seat (such as ribs crossing (spanning) theexhalation opening) during exhalation so that air may escape from themouthpiece. To the contrary, the disk is sucked and consequently pressedagainst the valve seat during inhalation so that no air may enter themouthpiece during inhalation.

In some embodiments, the filter may be integrated into the mouthpiece.In further embodiments, the body of the mouthpiece and the filter basemay be an integrated one-piece unit. To put it differently, in theseembodiments, the body of the mouthpiece and the filter base are oneelement and are not detachable from each other. Due to thisconfiguration, the tube connecting the body and the filter may be keptas short as possible. Therefore, the overall height of the mouthpiececan be reduced so that the filter does not form a visual obstruction forthe user enabling him/her to e.g. read and watch television. Inaddition, the number of parts is significantly reduced as compared tothe configuration as described with respect to FIGS. 1 and 2, nowconsisting of three parts only, the integrated one-piece unit consistingof the body and the filter base, the filter material and the filter top.In addition, the length may be reduced, whereby dead spaces areminimized.

In a particular embodiment, the integrated one-piece unit is aninjection molded part. Thus, the mouthpiece may be cost efficientlymanufactured.

In addition, the overall length may be reduced in a mouthpiece asdescribed above, whereby dead spaces are minimized. According to anaspect, this is assisted in that a distance between the center line ofthe filter base and the inhalation opening of the mouthpiece as seen ina side view is at least 30 mm or in another aspect at least 35 mm, butnot more than 50 mm, in another aspect not more than 40 mm. Thus, it maybe ensured that there is still enough space between the filter base andthe inhalation opening to accommodate the nose of a user without thenose touching the filter base but that the overall length of themouthpiece is minimized.

The integration of the filter base into the body of the mouthpiece toform the integrated one-piece unit according to the embodiments asdescribed above enables a reduction in the overall height of themouthpiece to avoid a visual obstruction for the user during inhalation(see above). According to one aspect, the height of the mouthpiece asseen in a side view is not more than 90 mm, and according to anotheraspect not more than 85 mm, and in one particular embodiment less than82 mm. For example, the maximum height may be 81.5 mm.

In one particular aspect, a retaining rib of the mouthpiece for beingengaged behind the teeth of a user is provided on an upper side of thebody and/or on a lower side of the body adjacent to the inhalationopening. Such a retaining rib facilitates hands free use of thenebulizer.

In order to even ergonomically improve the mouthpiece, one aspectsuggests a front edge of the body surrounding the inhalation openingwhich is curved in a plan view and/or a side view. Thus, the inhalationopening is shaped like the mouth of a fish.

Moreover and according to one aspect, the inlet port may be conical tobe force-fittingly connectable to a boss of the nebulizer (similar to aLuer taper or Luer Lock system). Such a configuration of the interfacebetween the mouthpiece and the nebulizer in principle allows anyorientation of the mouthpiece relative to the nebulizer, e.g. with thefilter directed upward, downward, towards the sides or tilted. Incombination with integrated one-piece unit, the orientation of themouthpiece at the nebulizer may be advantageously determined by theconfiguration of the filter base and/or the configuration of theinhalation port of the mouthpiece despite this general possibility. Forexample, the filter base may be configured to interfere with the chamberof the nebulizer when the mouthpiece is rotated about the boss of thenebulizer preventing or limiting such rotation.

In another example, the inhalation opening may be oval-shaped in a frontview, the oval shape having a minor axis and a major axis, wherein thefilter base (and/or the tube connecting the body and the filter base)extends from the body in a direction along the minor axis. Thus, only anorientation in which the filter is directed upward (or downward) isallowed.

In one aspect, the aerosol generator, the chamber and the mouthpiece maybe arranged in that order along the longitudinal direction of thenebulizer. Thus, the nebulizer as such is already relatively long. Yet,by reducing the overall length of the mouthpiece along the longitudinaldirection as described above, the overall length of the nebulizer may beminimized. Accordingly, the lever arm when holding the nebulizer withthe teeth at the inhalation opening of the mouthpiece may be reducedfacilitating hands-free inhalation.

According to a further aspect, the nebulizer further comprises a fluidreservoir or an interface configured to connect a fluid reservoir asdescribed above, wherein the aerosol generator comprises a vibratablemembrane having a plurality of apertures (see above) and separating thefluid reservoir and the chamber.

According to a further aspect, the fluid reservoir or the interface andthe membrane are arranged in that order along the longitudinal directionof the nebulizer. When the fluid reservoir or the interface and themembrane are arranged in that order along the longitudinal direction ofthe nebulizer, the general length of the nebulizer is increased. Yet, itis possible to shorten the mouthpiece by integrating the filter baseinto the mouthpiece as explained above so that the overall length of thenebulizer can be minimized.

Similar applies to the case in which the chamber has a length (Lc) alongthe longitudinal direction of the nebulizer between 30 mm and 100 mm,particularly 50 mm to 100 mm and more particularly not less than 70 mm,such as not less than 80 mm or not less than 90 mm. Again, the use ofsuch a chamber which is beneficial for providing a sufficiently largebolus in the chamber which is to be inhaled by the user lengthens thenebulizer and, hence, the lever arm when the nebulizer is held by theteeth at the inhalation opening of the mouthpiece. Due to thepossibility to shorten the mouthpiece including the filter this leverarm may again be reduced in length or minimized.

According to one aspect, the chamber has an ambient opening cooperatingwith a one-way valve allowing ambient air to enter the chamber fromoutside of the nebulizer upon inhalation of a patient through theinhalation opening of the mouthpiece.

As previously indicated, the mouthpiece and the nebulizer describedherein are useful for the administration or nebulization/aerosolizationof the pharmaceutical compositions for use according to the presentinvention comprising an inhalable immunosuppressive macrocyclic activeingredient such as tacrolimus or cyclosporine A, especially cyclosporineA (CsA).

Further features and aspects of the invention, particularly of thenebulizer and mouthpiece useful for the administration of thepharmaceutical compositions for use according to the present inventionare described in further detail below with respect to particularexamples making reference to the accompanying drawings. In the severaldrawings, the same reference numerals have been used for the same andthe like elements.

DETAILED DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 show a nebulizer 100 of a predevelopment similar to theone described in EP 1 927 373 B1. So as to provide an exhalation filter30, it had first been conceived to connect a T-shaped adapter 120 at aconnection port 121 to a chamber 105 of the nebulizer 100 fortemporarily accommodating the aerosol generated by the aerosol generator101 (see FIG. 5). A mouthpiece 40 is connected to the adapter 120 at aboss 122 opposite to the connection port 121. Moreover, an exhalationfilter 30 comprising a filter base 31, a filter top 33 detachablyconnected to the filter base 31 and a filter material 32 providedbetween the filter base 31 and the filter top 33 is provided. The filterbase 31 is connected to a filter connection port 123 of the adapter 120located between the connection port 121 and the boss 122.

This approach has however been conceived disadvantageous for severalreasons. First of all, if the filter is directed upward (not shown), thefilter is positioned closely in front of the user's nose and eyes. Thisis due to its height perceived uncomfortable, particularly if the userintends to read or watch television during inhalation.

The attempt to rotate the filter to the right (alternatively to theleft) as shown in FIG. 1 or so as to be directed downward leads to theproblem that the nebulizer may no longer be placed on a horizontalsurface because of the dimensions of the filter interfering with thehorizontal surface. Positioning the filter in a tilted position, asshown in FIG. 2, leads to instability of the nebulizer when being placedon a horizontal surface. Thus, handling of the nebulizer is impaired.Even further, this configuration employs a plurality of parts, namelythe T-shaped adapter, the filter base, the filter material, the filtertop and the mouthpiece (5 parts in total). This is perceiveddisadvantageous in handling the nebulizer as it needs to be disassembledfor cleaning and subsequently again be assembled for use. Moreover, thisconfiguration significantly increases the overall length Lo of thenebulizer. However, such nebulizers are often used hands free by holdingthe nebulizer at the inhalation opening of the mouthpiece by means ofthe teeth. Yet, the longer the nebulizer is, the longer is the lever armand the more difficult it is to use the nebulizer hands free. The sameholds true if the filter is positioned in the tilted position as shownin FIG. 2 and if rotated to one side as shown in FIG. 1. These positionsinduce a rotational force on the teeth which is perceived uncomfortable.

Finally, this configuration leads to an increased dead space from theconnection port 121 to the inhalation opening 42 at the mouthpiece 40 inwhich the aerosol may deposit and be washed out onto the filter duringexhalation and, thus, be wasted.

In specific embodiments, the mouthpiece 40 according to component c) ofthe aerosol generator 100 comprises:

-   -   a body 46 defining a fluid path 47 from an inlet port 41        connectable to the nebulizer 100 to an inhalation opening 42 to        be received in the mouth of the user; and    -   an exhalation filter 30 having a filter base 31 in fluid        communication with the fluid path 47, a filter top 33 detachably        connected to the filter base and a filter material 32 provided        between the filter base and the filter top, wherein the filter        top has an exhalation opening 36 cooperating with a one-way        valve 39 allowing exhaustion of fluid from the fluid path        through the filter material to the outside of the mouthpiece        upon exhalation of a patient through the inhalation opening;        wherein the body and the filter base are an integrated one-piece        unit.

The drawings show a nebulizer 100 comprising an aerosol generator 101(see FIG. 5) and a chamber 105 for temporarily accommodating the aerosolgenerated by the aerosol generator. In the example, the aerosolgenerator 100 comprises a vibratable membrane 110 having a plurality ofapertures in a central region 111. Moreover, a piezoelectric ring 112 isprovided to vibrate the membrane 110.

In addition, the nebulizer 100 comprises a fluid reservoir 103 applyinga liquid (such as a liquid pharmaceutical composition for use accordingto the present invention) to one side of the central region 111 of themembrane 110 containing the apertures (see FIG. 5). The fluid reservoir103 is closed by a lid 104. In general, such a nebulizer is disclosed inEP 1 927 373 B1 and EP 1 353 759 B1. Instead of a fluid reservoir it isalso conceivable to provide an interface such as a needle or collarconfigured to connect a fluid reservoir such as an ampoule. Such systemis for example disclosed in EP 1 919 542 B1.

In use, a liquid or fluid, or more specifically the pharmaceuticalcompositions for use according to the present invention, may be appliedto the one side of the membrane 110 (aerosol generator) and is passedthrough the apertures by vibrating the membrane via the piezoelectricelement 112 whereby the aerosol is introduced (ejected) into the chamber105. Thus, the membrane 110 (aerosol generator) is disposed between thefluid reservoir 103 and the chamber 105. The chamber 105 is configuredfor temporarily accommodating the aerosol generated by the membrane 110as a bolus to be inhaled by the subject or patient.

A longitudinal end of the chamber 105 opposite to the end at which themembrane 110 is disposed comprises a boss 106 defining a dischargeopening and being circular in cross section. The boss 106 may becylindrical or tapered resembling a male taper similar to a Luer taperSystem.

Further, the chamber 105 resembles a stand enabling to place thenebulizer 100 on a horizontal surface such as a table.

In addition, ambient openings 113 are disposed at one end of the chamber105 close to the aerosol generator 101. These openings 113 cooperatewith a one-way valve 114 such as flaps or reed valves allowing ambientair to enter the chamber 105 upon inhalation of a patient.

If the nebulizer 100 is to be used with a liquid or fluid, such as aliquid pharmaceutical composition for use according to the presentinvention containing a compound that may be detrimental to individualsstaying in the environment in which the user inhales, there is a need toimplement an exhalation filter 30.

In the predevelopment it was conceived to use a T-shaped adapter 120 toattach the exhalation filter 30. The T-shaped adapter 120 comprises aninlet port 121 being circular in cross section. The inlet port 121 iscylindrically shaped or tapered resembling a female taper similar to aLuer taper. The T-shaped adapter 120 is connected by force fit with itsinlet port 121 to the boss 106.

An outlet port 122 is disposed opposite to the inlet port 121. Theoutlet port 122 is configured similar to the boss 106 and is, hence,also circular in cross section and may be cylindrically shaped ortapered resembling a male taper of a Luer taper System.

A filter connection port 123 is disposed at an intermediate positionbetween the inlet port 121 and the outlet port 122 and extendssubstantially perpendicular to a direction from the inlet port 121 tothe outlet port 122 defining the T-shape. The filter connection port 123is circular in cross section and may be cylindrically shaped or taperedresembling a male taper of a Luer taper System.

The exhalation filter 30 comprises a filter base 31, a filter material32 (see FIGS. 4 and 5) and a filter top 33. The filter base 31 comprisesa connecting tube 34 which is circular in cross section and may eitherbe cylindrically shaped or tapered resembling a female Luer taper.Accordingly, the exhalation filter 30 may be connected to the filterconnecting port 123 by force fit.

The filter material 32 may be made of polypropylene or the like. In oneexample, the filter may be made of blended synthetic fibers for exampleattached to polypropylene spun bonded scrim. The filter may typicallyhave a thickness of between 1.5 mm to 5.5 mm or 2 mm to 5 mm or about3.5 mmm. The air permeability at 200 Pa may be from about 400 to about600 L/m²s and/or an air flow resistance may be about 46.0 PA at a mediumvelocity of 9.5 m/min. An exemplary filter is Microstat+250 MED sold byRiensch & Held, Germany. The filter material 32 is sandwiched betweenthe filter base 31 and the filter top 33 as will be apparent from FIG.5. Thus, the filter base 31 of the filter top 33 form a compartmentaccommodating the filter material 32.

The filter top 33 is detachably mounted to the filter base 31 using forexample a snap fit. The filter material may be changed by detaching thefilter top 33 from the filter base 31.

Moreover, the filter top may comprise another boss 35 allowingconnecting a tube or other equipment. Yet, this boss 35 may as well beomitted for example to reduce the device height.

Further, an exhalation opening 36 is provided in the filter top 33. Theexhalation opening 36 may be circular in cross section. In one aspect, aplurality of radial ribs 37 (FIG. 5) extend across the exhalationopening 36 and a pin 38 is formed in a center thereof. A one-way valve39 (in the present aspect a disk made of a flexible material) is fixedto the pin 38 so as to be disposed on a side of the ribs 37 opposite tothe compartment and the filter material 32. Thus, the one-way valve 39allows fluid to flow from the compartment between the filter base 31 andthe filter top 33 valve 39 opens (the disc 39 lifts from the radial ribs37 allowing the fluid to pass between the ribs 37 through the exhalationopening 36 to the outside). However, the valve 39 blocks the flow offluid in the opposite direction from the environment toward thecompartment in that it closes (the disc 39 is pressed against the radialribs 37 closing the openings between the ribs 37 and hence blocking theexhalation opening 36).

Moreover, FIGS. 1 and 2 show a mouthpiece 40 having a connecting portion41 circular in cross section and cylindrically shaped or taperedresembling a female Luer taper, like a tube connector used in intensivecare units. The connecting portion 41 is connected to the outlet port122 of the T-shaped adapter 120 by force fit. This may provide anairtight seal at the connection between the connecting port 41 and theT-shaped adapter 120.

An inhalation opening 42 may be provided opposite to the connectingportion 41. The inhalation opening 42 is oval in cross section as bestvisible from FIG. 2. Thus, the inhalation opening 42 comprises a majoraxis substantially oriented horizontally and/or parallel to the stand107 and a minor axis extending perpendicularly to the major axis.

In this context, the mouthpiece 40 contains a taper 43 in which themouthpiece 40 changes its cross section from a circular cross-section atthe connecting portion 41 to the oval cross-section of the inhalationopening 42. Thus, the mouthpiece 40 tapers at an intermediate position43 defining a substantially flat portion 44 to be accommodated in themouth of a subject or patient.

Further, retaining ribs 45 are formed on the long sides of the ovalcross-section adjacent the inhalation opening 42 extending substantiallyperpendicular from the portion 44. Thus, the teeth may catch or engagebehind the retaining ribs 45 and the user may hold the entire nebulizerwith his/her teeth and use it hands free.

This predevelopment, even though providing the required function offiltering exhausted air, has, however, disadvantages. For example, ifthe filter 30 is directed upward (not shown), the filter is positionedclosely in front of the user's nose and eyes. In other words, the heightH of the nebulizer is too large. This is perceived uncomfortable,particularly if the user intends to read or watch television duringinhalation. The attempt to rotate the filter to the right (alternativelyto the left) as shown in FIG. 1 or so as to be directed downward leadsto the problem that the nebulizer may no longer be placed on ahorizontal surface in view of the stand 107 because of the dimensions ofthe filter. Positioning the filter in a tilted position, as shown inFIG. 2, leads to instability of the nebulizer when being placed on ahorizontal surface. In particular in this configuration, the nebulizerwould tend to tilt over. Thus, handling of the nebulizer is impaired.

Even further, this configuration employs a plurality of parts, namelythe T-shaped adapter 120, the filter base 31, the filter material 32,the filter top 33 and the mouthpiece 40 (making in total 5 parts). Thisis perceived disadvantageous in handling the nebulizer as it needs to bedisassembled for cleaning and subsequently again be assembled for useand may lead to an inaccurate assembly of parts and to misuse withoutfilter and exhalation valve.

Moreover, this configuration significantly increases the overall lengthLo of the nebulizer. However, such nebulizers are often used hands freeas explained above by holding the nebulizer at the inhalation opening ofthe mouthpiece using the retaining ribs 45 by means of the teeth. Yet,the longer the nebulizer is, the longer is the lever arm and the moredifficult it is to use the nebulizer hands free. This effect is evenmore severe when a relatively long mixing chamber 105 having a length Lcbetween 80 mm and 100 mm is used.

Finally, this configuration leads to an increased dead space from theconnection port 121 to the inhalation opening 42 at the mouthpiece 40 inwhich the aerosol may deposit and be washed out onto the filter 32during exhalation, thus, be wasted.

Most of these problems may be alleviated in particular, when the adapter120 and the filter base 31 have been integrated into the mouthpiece 40as particularly shown in FIGS. 3 to 5 as one-piece unit with a definedconnector to the chamber 105.

Thus, the mouthpiece 40 according to an aspect comprises a body 46having the inlet port 41 resembling the connection port 121 of theadapter 120. The inlet port 41 is, thus, connectable to the boss 106 ofthe chamber 105 of the nebulizer 100 by force fit.

The body 46 defines a fluid path 47 from the inlet port 41 to theinhalation opening 42.

In addition, in the embodiments as shown in FIGS. 3 to 5 the filter base31 is integrally formed with the body 46. In particular, the body 126comprises a nipple 48 perpendicularly extending from the body 46 in adirection of the minor axis of the inhalation opening 42. The nipple 48resembles the filter connection boss 123 and connection port 35. Thus,the body together with the exhalation filter 30 forms a further fluidpath 49 from an opening 50 opening into the fluid path 47 through theexhalation filter 30 passing the filter material 32 and exiting throughthe exhalation opening 36.

Thus, according to this preferred embodiment, the filter base 31, thenipple 48 and the body 46 including the inhalation opening 42 and theconnection port 41 define an integrated one-piece unit. In one aspect,this integrated one-piece unit is formed by injection molding.Accordingly, in this embodiment the integrated one-piece unit of thebody (46) and the filter base (31) are an integrated one-piece unit isan injection molded part.

The filter material 32 and the filter top 33 may remain the same aspreviously described. Similar applies to the configuration of themouthpiece with respect to the inhalation opening 42, the ribs 45, thetapering 43 and the portion 44.

However, and in order to even further improve the ergonomic shape of themouthpiece 40 adjacent to the inhalation opening 42, the edge 51bordering the inhalation opening 42 is shaped similar to the mouth of afish. To put it differently, the edge is curved inwardly in a side viewand outwardly in a top view as best visible from FIG. 3.

In a further embodiment, the opening 42 may have at least two ribsjuxtaposed to each other in the longitudinal direction L to ensure abetter hold with the teeth.

In use, a liquid, namely the pharmaceutical composition for useaccording to the present invention, is nebulized by the aerosolgenerator 101 into the chamber 105 were the aerosol is temporarilystored. Upon inhalation of a user through the inhalation opening 42,ambient air flows through the openings 113, wherein the valves 114 openinto the chamber 105 and entrains the aerosol, which flows from thechamber 105 through the boss 106 and the connection port 41 through thefluid path 47 and is inhaled through the inhalation opening 42 asindicated by the arrows I in FIG. 5. During inhalation, the disk 39closes the openings between the radial ribs 37 and, hence, theexhalation opening 36 so that no ambient air may enter through theexhalation opening 36.

Upon exhalation, the exhaled air from the patient or user is introducedthrough the inhalation opening 42 and flows through the fluid paths 47and 49 as indicated by the arrow E in FIG. 5 through the opening 50 intothe exhalation filter 30 passes the filter material 32 and exits theinhalation filter 30 through the exhalation opening 36. During thisprocess, the disk 39 lifts from the radial ribs 37 and allows theexhaled and filtered air to pass and exit through the exhalation opening36. During this process, the valves 14 close the openings 113 so thatthe only possibility for the exhaled air to escape is through the filter30. Especially fluids that are partly toxic should be avoided to be setout to the environment for assistant persons.

Due to the preferred integration of the filter base 31 and the adapter120 into the mouthpiece 40, particularly into the body 46 thereof, thelength LM of the mouthpiece 40 can be kept short as compared to thelength of the adapter 120 and the mouthpiece 40 shown in FIGS. 1 and 2.Accordingly, the overall length Lo of the nebulizer 100 can be reduced.As a result, the lever arm can be shortened and it is easier to use thenebulizer 100 free-hand by retaining the nebulizer 100 via the teethengaging with the retaining ribs 45 and thereby support the nebulizer100.

The preferred setup as a one-pieced unit, of the filter base 31, thenipple 48 and the body 46 including the inhalation opening 42 and theconnection port 41, ensures that the entire exhaled air including thegenerated aerosol is filtered before the aerosol is exhausted from thedevice.

In addition, by keeping a distance D between the filter base 131 andinhalation opening 42 as seen in the side view (FIG. 5) between 30 and50 millimeters, preferably between 35 millimeters and 40 millimeters,there is sufficient space to accommodate the nose of a user without thenose touching the inhalation filter 30 at the same time reducing theoverall length LM of the mouthpiece 42 to its minimum.

In addition, because of the incorporation of the filter connecting port123 and the connecting tube 34 into the body 46, the filter base 31 maybe brought closer to the body 46 whereby the overall height H in sideview may be reduced to not more than 90 mm. In the shown example, themaximum height H is 81.5 mm. When omitting the boss 35, the height mayeven be further reduced to the height H₁. The overall height from thefilter base to the exhalation filter opening of the mouthpiece will befurther reduced. As one aspect, the height of the mouthpiece as seen ina side view (FIG. 5) is not more than 75 mm, and according to anotheraspect not more than 70 mm, and in one particular embodiment less than57 mm. For example, the maximum height may be 56.2 mm.

As a result, the suggested aspects according to this embodiment providesignificant advantages particularly as compared to the internalpredevelopment as described above.

The inlet port 41 has been described above as forming a female taper ofa Luer taper (the boss 106) cooperating with a male taper (the boss106). Yet, the inlet port 41 may as well be configured as a male taperof a Luer taper cooperating with a female taper at the chamber 105.

LIST OF REFERENCE NUMERALS

30 exhalation filter

31 filter base

32 filter material

33 filter top

34 connecting tube

35 connecting port

36 exhalation opening

37 radial ribs

38 pin

39 one-way valve

40 mouthpiece

41 inlet port

42 inhalation opening

43 tapering

44 flat portion

45 retaining rib

46 body of mouthpiece

47 fluid path

48 nipple

49 further fluid path

50 opening of further fluid path

51 front edge of the body

100 nebulizer

101 aerosol generator

103 fluid reservoir

104 lid

105 chamber

106 boss (of the nebulizer)

107 stand

110 vibratable membrane

111 central region of the membrane

112 piezoelectric element

113 ambient opening

114 one-way valve

120 T-shaped adapter

121 connection port

122 boss

123 filter connection port

The nebulizer and mouthpiece as described in detail above allows for theadministration of the pharmaceutical compositions for use according tothe present invention. Especially when provided in form of a solution,colloidal formulation or suspension, the nebulizer and mouthpiece allowfor generating the aerosol comprising the present pharmaceuticalcompositions to be administered in a high fraction of droplets orparticles which are able to reach the periphery of the lungs (“FineParticle Fraction”; FPF). In specific embodiments, these droplets orparticles have a mass average particle diameter of equal or lower than 5μm as measured e.g. by laser diffraction using a Malvern MasterSizer Xor using a multistage cascade impactor such as the Anderson CascadeImpactor (ACI) or the Next Generation Impactor (NGI).

In specific embodiments of the pharmaceutical composition for useaccording to the present invention, the aerosol to be administered tothe patient comprises droplets wherein at least 50%, more specificallyfrom about 60 to about 95% or more specifically from about 70% to about90% of the total number of droplets have a diameter of up to 5 μm (asmeasured by laser diffraction or by a multistage cascade impactor asdescribed above) when measured with a aqueous composition comprisingL-CsA in a concentration of 4 mg/mL as described in Example 2.2 below.

The nebulizer and mouthpiece as described in detail above further allowfor the administration of the pharmaceutical compositions for useaccording to the present invention with a higher percentage of drugavailable as delivered dose (DD) and respirable dose (RD) compared toconventional nebulizers such as jet nebulizers. The term ‘delivereddose’ (DD) as used herein means the fraction of the active ingredientfilled into the nebulizer for aerosolization and inhalation which isactually delivered to the targeted tissue, in case of the presentinvention to the lungs or, more specifically to the peripheral tissuesof the lung. Accordingly, in specific embodiments of the presentinvention, the inhalable immunosuppressive macrocyclic activeingredient, preferably cyclosporine A (CsA) is delivered to the lungs(or the lung) of the subject in an amount of at least 60% or even atleast 70%, more specifically in an amount in the range of from about 70%to about 80% of the amount administered to the subject.

Furthermore, the nebulizer and mouthpiece as described above allow forthe administration of the pharmaceutical compositions for use at a hightotal output rate (TOR) which is typically above about 150 mg/mincorresponding to about 0.15 mL/min for liquid compositions with arelative density of about 1, with regard to the final pharmaceuticalcomposition to be nebulized and administered. In specific embodiments,the inhalable immunosuppressive macrocyclic active ingredient isadministered to the subject at a total output rate (TOR) of at least 200mg/min or more specifically at a total output rate in the range of fromabout 200 mg/min to about 300 mg/min or of from about 200 to about 250mg/min. Accordingly, the nebulizer and mouthpiece as described aboveallows for a short nebulization time of the present liquidpharmaceutical composition. Obviously, the nebulization time will dependon the volume of the composition which is to be aerosolized and on theoutput rate.

The volume of a unit dose of the pharmaceutical compositions for useaccording to the present invention is preferably low in order to allowshort nebulization times. The volume, also referred to as the volume ofa dose, or a dose unit volume, or a unit dose volume, should beunderstood as the volume of the pharmaceutical composition to beaerosolized or nebulized which is intended for being used for one singleadministration. A unit dose is defined as the dose of cyclosporine A inthe formulation filled in the nebulizer for one single administration.Specifically, the volume of a unit dose may be less than 10 mL or less.Preferably, the dose unit volume is in the range from about 0.3 to about3.5 mL, more preferably about 1 to about 3 mL. For example, the volumeis about 1.25 mL or about 2.5 mL. In case the formulation is obtainedafter reconstitution, the volume of the saline solution forreconstitution should be adapted according to the desired volume of thereconstituted formulation.

The unit dose of the macrocyclic immunosuppressive active ingredient,preferably CsA typically is within the range of from about 1 mg to about15 mg. In specific embodiments, a unit dose of the chosen activeingredient, preferably CsA is about 5 mg or about 10 mg.

Accordingly, in specific embodiments, 1 mL of the pharmaceuticalcomposition comprising an inhalable immunosuppressive macrocyclic activeingredient is aerosolized (nebulized) within a period of up to about 5min, preferably of up to about 4 min, specifically in cases in which aliquid aqueous composition comprising CsA in liposomally solubilizedform at a concentration of 4 mg/mL is administered.

In addition to providing a high delivered dose and having shortnebulization times, the nebulizer and mouthpiece for administering thepresent pharmaceutical compositions is constructed in such way thatcontamination of the environment with the immunosuppressive macrocyclicactive ingredient such as CsA or tacrolimus is prevented by theexhalation filter of the mouthpiece. Such exhalation filter may reduceor avoid emission of the exhaled amount of the macrocyclicimmunosuppressive active ingredient such as CsA or tacrolimus to theenvironment. However, due to the high percentage of the droplets of theaerosol actually delivered to the targeted tissue as described above,the nebulizer and mouthpiece to be used in connection with the presentinvention allows for the significant reduction of the exhaled activeingredient. Accordingly, in specific embodiments of the presentinvention the amount of the inhalable immunosuppressive macrocyclicactive ingredient exhaled by the subject is up to 10%, more specificallyfrom about 4% to about 8% of the total amount of active ingredientfilled into the nebulizer during standardized simulated breathing, whichmeasure the amount, which is normally administered to the subject andcould be collected on the exhalation filter.

Accordingly, in a specific embodiment, the present invention providesfor a pharmaceutical composition comprising an inhalableimmunosuppressive macrocyclic active ingredient, specificallycyclosporine A, for use in the prevention or treatment of a pulmonarydisease or condition in a subject,

wherein the pharmaceutical composition is administered to the subject byinhalation in form of an aerosol, and

-   -   wherein the aerosol is generated by nebulization of the        pharmaceutical composition using a nebulizer (100), the        nebulizer comprising:    -   a) an aerosol generator (101) comprising:        -   a fluid reservoir (103) for holding the pharmaceutical            composition or an interface configured to connect a fluid            reservoir, and        -   a vibratable membrane (110) having a plurality of apertures,            the apertures being adapted to produce an aerosol comprising            droplets having a mass median aerodynamic diameter (MMAD) of            up to about 4.0 μm as measured with a 0.9% (w/v) aqueous            solution of sodium chloride;    -   b) a chamber (105) for temporarily accommodating the aerosol        generated by the aerosol generator (101), the chamber having an        inner lumen with a volume in the range of from about 50 to about        150 ml; and    -   c) a mouthpiece (40) for delivering the aerosol supplied by the        nebulizer (100) to the subject, the mouthpiece having an        exhalation filter (30),

wherein the inhalable immunosuppressive macrocyclic active ingredient isadministered to the subject at a total output rate (TOR) of at least 200mg/min and preferably wherein the amount of the inhalableimmunosuppressive macrocyclic active ingredient exhaled by the subjectis up to 10%, more specifically from about 4% to about 8% of the totalamount of active ingredient filled into the nebulizer (duringstandardized simulated breathing).

It should be understood that these specific embodiments also, as allother embodiments may be combined with other features, embodimentsand/or aspects as disclosed herein in connection with, for example, thepharmaceutical composition and/or the inhalable macrocyclicimmunosuppressive active ingredient to be administered as described indetail above, and/or in connection with the nebulizer and the mouthpieceas described herein. Furthermore, these embodiments may or may not becombined with specific features of the administration of thepharmaceutical composition such as, for example, with the specificembodiment in which 1 mL of the pharmaceutical composition comprising aninhalable immunosuppressive macrocyclic active ingredient is aerosolized(nebulized) within a period of up to about 5 min, preferably of up toabout 4 min, specifically in cases in which a liquid aqueous compositioncomprising CsA in liposomally solubilized form at a concentration ofabout 4 mg/mL is administered, as described above.

The pharmaceutical compositions for use according to the invention canbe administered according to a pre-determined dosing regimen.Especially, the composition can be administered a specific number oftimes during each week of treatment. For example, the pharmaceuticalcomposition can be administered three times per week. Preferably, theformulation is administered daily. Even more preferred, the compositionis administered twice daily.

In a further aspect, the present invention provides for a method forpreventing or treating a pulmonary disease or condition in a subject,the method comprising the step of administering an inhalableimmunosuppressive macrocyclic active ingredient to said subject byinhalation in form of an aerosol comprising the immunosuppressivemacrocyclic active ingredient,

-   -   wherein the aerosol is generated by nebulization of the        pharmaceutical composition using a nebulizer (100), the        nebulizer comprising:    -   a) an aerosol generator (101) comprising:        -   a fluid reservoir (103) or an interface configured to            connect a fluid reservoir, and        -   a vibratable membrane (110) having a plurality of apertures,            the apertures being adapted to produce an aerosol comprising            droplets having a mass median aerodynamic diameter (MMAD) of            up to about 4.0 μm as measured with a 0.9% (w/v) aqueous            solution of sodium chloride;    -   b) a chamber (105) for temporarily accommodating the aerosol        generated by the aerosol generator, the chamber having an inner        lumen with a volume in the range of from about 50 to about 150        ml; and    -   c) a mouthpiece (40) for delivering the aerosol supplied by the        nebulizer 100 to the subject, the mouthpiece having an        exhalation filter (30).

More specifically, the method for preventing or treating a pulmonarydisease or condition may further comprise the step of

-   -   providing a pharmaceutical composition comprising an inhalable        immunosuppressive macrocyclic active ingredient in form of an        aqueous liquid solution.

In connection with this further aspect of the present invention as wellas with regard to the further aspects as described below, it is to beunderstood that all features, embodiments and aspects of the presentinvention as described in detail above for the first aspect of theinvention as well as all combinations thereof equally apply inconnection with the present method of treatment as well as for the usesof the pharmaceutical composition of the present invention as well asthe kit as described further below.

In a third aspect, the present invention provides for the use of aninhalable immunosuppressive macrocyclic active ingredient in themanufacture of a pharmaceutical composition for the prevention ortreatment of a pulmonary disease or condition in a subject byinhalation, wherein the pharmaceutical composition is administered tothe subject by inhalation in form of an aerosol,

-   -   wherein the pharmaceutical composition is administered to the        subject by inhalation in form of an aerosol, and    -   wherein the aerosol is generated by nebulization of the        pharmaceutical composition using a nebulizer (100), the        nebulizer comprising:    -   a) an aerosol generator (101) comprising:        -   a fluid reservoir (103) for holding the pharmaceutical            composition or an interface configured to connect a fluid            reservoir, and        -   a vibratable membrane (110) having a plurality of apertures,            the apertures being adapted to produce an aerosol comprising            droplets having a mass median aerodynamic diameter (MMAD) of            up to about 4.0 μm as measured with a 0.9% (w/v) aqueous            solution of sodium chloride;    -   b) a chamber (105) for temporarily accommodating the aerosol        generated by the aerosol generator (101), the chamber having an        inner lumen with a volume in the range of from about 50 to about        150 ml; and    -   c) a mouthpiece (40) for delivering the aerosol supplied by the        nebulizer (100) to the subject, the mouthpiece having an        exhalation filter (30).

In a fourth aspect, the present invention provides a kit comprising

-   -   a pharmaceutical composition comprising an inhalable        immunosuppressive macrocyclic active ingredient for use in the        prevention or treatment of a pulmonary disease or condition in a        subject; and    -   a nebulizer (100), the nebulizer comprising:        -   a) an aerosol generator (101) comprising:            -   a fluid reservoir (103) for holding the pharmaceutical                composition or an interface configured to connect a                fluid reservoir, and            -   a vibratable membrane (110) having a plurality of                apertures, the apertures being adapted to produce an                aerosol comprising droplets having a mass median                aerodynamic diameter (MMAD) of up to about 4.0 μm as                measured with a 0.9% (w/v) aqueous solution of sodium                chloride;        -   b) a chamber (105) for temporarily accommodating the aerosol            generated by the aerosol generator (101), the chamber having            an inner lumen with a volume in the range of from about 50            to about 150 ml; and        -   c) a mouthpiece (40) for delivering the aerosol supplied by            the nebulizer (100) to the subject, the mouthpiece having an            exhalation filter (30).

In specific embodiments of the kit according to this aspect of theinvention, the pharmaceutical composition comprising an inhalableimmunosuppressive macrocyclic active ingredient for use in theprevention or treatment of a pulmonary disease or condition in a subjectis provided in form of a preformed liquid aqueous composition.

In further specific embodiments of the kit according to this aspect ofthe invention, the pharmaceutical composition comprising an inhalableimmunosuppressive macrocyclic active ingredient for use in theprevention or treatment of a pulmonary disease or condition in a subjectis provided in form of a lyophilisate comprising the inhalableimmunosuppressive macrocyclic active ingredient and a sterile liquidaqueous carrier liquid for the reconstitution of the lyophilisate toform a liquid pharmaceutical composition.

The following list of numbered items are embodiments comprised by thepresent invention:

-   1. A pharmaceutical composition comprising an inhalable    immunosuppressive macrocyclic active ingredient for use in the    prevention or treatment of a pulmonary disease or condition in a    subject,    -   wherein the pharmaceutical composition is administered to the        subject by inhalation in form of an aerosol, and    -   wherein the aerosol is generated by nebulization of the        pharmaceutical composition using a nebulizer (100), the        nebulizer comprising:    -   a) an aerosol generator (101) comprising:        -   a fluid reservoir (103) for holding the pharmaceutical            composition or an interface configured to connect a fluid            reservoir, and        -   a vibratable membrane (110) having a plurality of apertures,            the apertures being adapted to produce an aerosol comprising            droplets having a mass median aerodynamic diameter (MMAD) of            up to about 4.0 μm as measured with a 0.9% (w/v) aqueous            solution of sodium chloride;    -   b) a chamber (105) for temporarily accommodating the aerosol        generated by the aerosol generator (101), the chamber having an        inner lumen with a volume in the range of from about 50 to about        150 ml; and    -   c) a mouthpiece (40) for delivering the aerosol supplied by the        nebulizer (100) to the subject, the mouthpiece having an        exhalation filter (30).-   2. The pharmaceutical composition for use according to item 1,    wherein the pulmonary disease or condition is selected from the    group consisting of asthma, refractory asthma, chronic obstructive    bronchitis, parenchymal, fibrotic and interstitial lung diseases and    inflammations, bronchiolitis obliterans (BOS), and acute and chronic    organ transplant rejection reactions after lung transplantation and    the diseases resulting therefrom.-   3. The pharmaceutical composition for use according to item 1 or 2,    wherein the pulmonary disease or condition is bronchiolitis    obliterans (BOS), optionally after acute and chronic organ    transplant rejection reactions after lung transplantation or after    hematopoietic stem cell transplantation (HSCT).-   4. The pharmaceutical composition for use according to any of the    preceding items, wherein the pulmonary disease or condition is    bronchiolitis obliterans (BOS) grade I or higher, specifically BOS    grade I or II, especially BOS grade I.-   5. The pharmaceutical composition for use according to any of the    preceding items, for use in the treatment of a pulmonary disease or    condition in a subject.-   6. The pharmaceutical composition for use according to any of the    preceding items, wherein the inhalable immunosuppressive macrocyclic    active ingredient is selected from cyclosporine A (CsA) and    tacrolimus.-   7. The pharmaceutical composition for use according to any of the    preceding items, wherein the inhalable immunosuppressive active    ingredient is cyclosporine A.-   8. The pharmaceutical composition for use according to any of the    preceding items, wherein the inhalable immunosuppressive active    ingredient is present in liposomally solubilized form (L-CsA).-   9. The pharmaceutical composition for use according to any of the    preceding items, wherein the composition is a liquid composition    comprising an aqueous liquid vehicle.-   10. The composition for use according to item 9, wherein the aqueous    liquid vehicle essentially consists of saline, preferably of saline    with a concentration of 0.25% (w/v).-   11. The pharmaceutical composition for use according to any    preceding item, comprising the immunosuppressive macrocyclic active    ingredient in a concentration in the range of from about 1 mg/mL to    about 10 mg/mL.-   12. The pharmaceutical composition for use according to any    preceding item, wherein the liquid aqueous composition comprises    cyclosporine A in liposomally solubilized form (L-CsA) in a    concentration in the range of from about 3 mg/mL to about 5 mg/mL.-   13. The pharmaceutical composition for use according to item 12,    wherein the liquid aqueous composition comprises cyclosporine A in    liposomally solubilized form (L-CsA) in a concentration in the range    of from about 3.8 mg/mL to about 4.2 mg/mL.-   14. The pharmaceutical composition for use according to any    preceding item, wherein the aqueous liquid composition comprising    the inhalable immunosuppressive macrocyclic active ingredient in    liposomally solubilized form is obtained by reconstitution of a    lyophilisate comprising the immunosuppressive macrocyclic active    ingredient and liposome forming structures.-   15. The pharmaceutical composition for use according to any    preceding item, wherein the composition comprises at least one    disaccharide selected from the group consisting of saccharose,    lactose and trehalose, preferably saccharose.-   16. The pharmaceutical composition for use according to item 15,    wherein the composition has a content of the at least one    disaccharide selected from the group consisting of saccharose,    lactose and trehalose, preferably saccharose, in the range of from    about 5 to about 15 wt.-%, preferably in the range of from about 7.5    to about 12.5 wt.-%, based on the total weight of the resulting    pharmaceutical composition.-   17. The pharmaceutical composition for use according to any of items    14 to 16, wherein the liposome-forming structures comprise a bilayer    membrane formed of a membrane-forming substance selected from the    group of phospholipids.-   18. The pharmaceutical composition for use according to any of item    14 to 17, wherein the liposome-forming structures are at least    partly present in unilamellar form.-   19. The pharmaceutical composition for use according to any of items    14 to 18, wherein the inhalable immunosuppressive macrocyclic active    ingredient is at least partially incorporated (or intercalated) in    the bilayer membrane of the liposome-forming structures.-   20. The pharmaceutical composition for use according to any of items    14 to 19, wherein the inhalable immunosuppressive macrocyclic active    ingredient, specifically wherein CsA is predominantly (for example    by at least about 90% or even at least about 95% to about 97.5%)    incorporated in the bilayer membrane of the liposome-forming    structures.-   21. The pharmaceutical composition for use according to any of items    17 to 20, wherein the membrane-forming substance selected from the    group of phospholipids is a mixture of natural phospholipids.-   22. The pharmaceutical composition for use according to any of items    17 to 21, wherein the membrane-forming substance selected from the    group of phospholipids is a lecithin containing unsaturated fatty    acid residues.-   23. The pharmaceutical composition for use according to any of items    17 to 22, wherein the membrane forming substance selected from the    group of phospholipids is a lecithin selected from the group    consisting of soy bean lecithin, Lipoid S75, Lipoid S100,    Phospholipon® G90, 100 or a comparable lecithin.-   24. The pharmaceutical composition for use according to any of items    14 to 23, wherein the composition further comprises at least one    solubility-enhancing substance selected from the group of non-ionic    surfactants.-   25. The pharmaceutical composition for use according to item 24,    wherein the at least one non-ionic surfactant is selected from the    group of polysorbates.-   26. The pharmaceutical composition for use according to item 24 or    25, wherein the solubility-enhancing substance selected from the    group of non-ionic surfactants is polysorbate 80.-   27. The pharmaceutical composition for use according to any of items    24 to 26, wherein the weight ratio of phospholipid to polysorbate is    selected in the range of from about 15:1 to about 9:1, preferably    between from about 14:1 to about 12:1, for example, about 13:1.-   28. The pharmaceutical composition for use according to any of items    24 to 27, wherein the weight ratio between the (sum of the)    phospholipid and the nonionic surfactant on the one hand and the    inhalable immunosuppressive macrocyclic active ingredient,    specifically cyclosporine A (CsA) on the other hand is selected in    the range of from about 5:1 to about 20:1, preferably from about 8:1    to about 12:1 and more preferably about 10:1.-   29. The pharmaceutical composition for use according to any of items    24 to 28, wherein the weight ratio between the phospholipid    (lecithin), the nonionic surfactant and the inhalable    immunosuppressive macrocyclic active ingredient, specifically    cyclosporine A (CsA) is between about 15:1:1.5 and about 5:0.3:0.5,    and preferably at about 9:0.7:1.-   30. The pharmaceutical composition for use according to any    preceding item, wherein the composition comprises one or more    further excipients.-   31. The pharmaceutical composition for use according to item 30,    wherein the one or more further excipients are selected from buffers    and chelating agents.-   32. The pharmaceutical composition for use according to any    preceding item, wherein the composition is in the form of a    dispersion with an osmolality in the range of from about 430 to    about 550 mOsmol/kg.-   33. The pharmaceutical composition for use according to any    preceding item, wherein the composition is in the form of a    dispersion with a polydispersity index (PI) as measured by photon    correlation spectroscopy up to about 0.50.-   34. The pharmaceutical composition for use according to item 32 or    33, wherein the dispersion is essentially free from visible    particles.-   35. The pharmaceutical composition for use according to any of items    32 to 34, wherein the dispersion comprises liposomes with a    z-average diameter as measured by photon correlation spectroscopy in    the range of from about 40 to about 100 nm.-   36. The pharmaceutical composition for use according to any    preceding item, wherein the vibratable membrane (110) separates the    fluid reservoir (103) and the chamber (105).-   37. The pharmaceutical composition for use according to any    preceding item, wherein the vibratable membrane (110) has a convex    shape curving towards the aerosol release side of the membrane.-   38. The pharmaceutical composition for use according to any    preceding item, wherein the vibratable membrane (110) has from about    100 to about 400 apertures per mm².-   39. The pharmaceutical composition for use according to any    preceding item, wherein the plurality of apertures of the vibratable    membrane (110) have a tapered shape narrowing towards the aerosol    release side of the vibratable membrane.-   40. The pharmaceutical composition for use according to any    preceding item, wherein the apertures of the vibratable membrane    (110) have an exit diameter of up to 4.0 μm as measured by scanning    electron microscopy (SEM).-   41. The pharmaceutical composition for use according to any    preceding item, wherein the aerosol generator (101) comprises a    piezoelectric element (such as a piezoelectric crystal as a    vibration generator).-   42. The pharmaceutical composition for use according to any    preceding item, wherein the inhalable immunosuppressive macrocyclic    active ingredient is delivered to the lungs (or the lung) of the    subject in an amount (Delivered dose, DD) of at least 70%, more    specifically in an amount in the range of from about 70% to about    80% of the amount administered to the subject.-   43. The pharmaceutical composition for use according to any    preceding item, wherein the inhalable immunosuppressive macrocyclic    active ingredient is administered to the subject at a total output    rate (TOR) of at least 200 mg/min, more specifically at a total    output rate in the range of from about 200 to about 250 mg/min.-   44. The pharmaceutical composition for use according to any    preceding item, wherein the amount of the inhalable    immunosuppressive macrocyclic active ingredient exhaled by the    subject is up to 10%, more specifically from about 4% to about 8% of    the total amount of active ingredient administered to the subject.-   45. The pharmaceutical composition for use according to any    preceding item, wherein the aerosol administered to the patient    comprises droplets and wherein at least 50%, more specifically from    about 60% to about 95% or more specifically from about 70% to about    90% of the total number of droplets have a diameter of up to 5 μm    (as measured by laser diffraction or by a multistage cascade    impactor as described above) when measured with a aqueous    composition comprising L-CsA in a concentration of 4 mg/mL.-   46. The pharmaceutical composition for use according to any    preceding item, wherein 1 mL of the pharmaceutical composition    comprising an inhalable immunosuppressive macrocyclic active    ingredient is aerosolized (nebulized) within a period of up to about    5 min, specifically in cases in which a liquid aqueous composition    comprising CsA in liposomally solubilized form at a concentration of    4 mg/mL is administered.-   47. The pharmaceutical composition for use according to any    preceding item, wherein the mouthpiece (40) comprises:    -   a body (46) defining a fluid path (47) from an inlet port (41)        connectable to the nebulizer (100) to an inhalation opening (42)        to be received in the mouth of the user; and    -   a filter (30) having a filter base (31) in fluid communication        with the fluid path (47), a filter top (33) detachably connected        to the filter base and a filter material (32) provided between        the filter base and the filter top, wherein the filter top has        an exhalation opening (36) cooperating with a one-way valve (39)        allowing exhaustion of fluid from the fluid path through the        filter material to the outside of the mouthpiece upon exhalation        of a patient through the inhalation opening;    -   wherein the body and the filter base are an integrated one-piece        unit.-   48. The pharmaceutical composition for use according to any of the    preceding items, wherein the aerosol generator (101), the chamber    (105) and the mouthpiece (40) are arranged in that order along the    longitudinal direction of the nebulizer (100).-   49. The pharmaceutical composition for use according to any of the    preceding items, wherein the fluid reservoir (103) or the interface    and the membrane (110) are arranged in that order along the    longitudinal direction of the nebulizer (100).-   50. The pharmaceutical composition for use according to any of the    preceding items, wherein the chamber (105) has a length (L_(C))    along the longitudinal direction of the nebulizer between 20 mm and    100 mm, particularly 50 mm to 100 mm.-   51. The pharmaceutical composition for use according to any of the    preceding items, wherein the chamber (105) has an inner lumen with a    volume in the range of from about 75 to about 125 ml.-   52. The pharmaceutical composition for use according to any of the    preceding items, wherein the chamber (105) cooperates with an    ambient opening (113) having a one-way valve (114) allowing ambient    air to enter the chamber (105) from outside of the nebulizer (100)    upon inhalation of a subject through the inhalation opening (42) of    the mouthpiece (40).-   53. The pharmaceutical composition for use according to any of items    47 to 52, wherein the integrated one-piece unit of the body (46) and    the filter base (31) are an integrated one-piece unit is an    injection molded part.-   54. The pharmaceutical composition for use according to any of items    47 to 53, wherein a distance (D) between the filter base (31) and    the inhalation opening (42) of the mouthpiece (40) as seen in a side    view is at least 30 mm, preferably at least 35 mm and not more than    50 mm, preferably not more 40 mm.-   55. The pharmaceutical composition for use according to any of items    47 to 54, wherein a maximum height (H) of the mouthpiece (40) as    seen in a side view is not more than 90 mm, preferably not more than    85 mm.-   56. The pharmaceutical composition for use according to any of items    47 to 55, wherein a retaining rib (45) of the mouthpiece (40) for    being engaged behind the teeth of a user is provided on an upper    side of the body (46) and/or on a lower side of the body (46)    adjacent to the inhalation opening (42).-   57. The pharmaceutical composition for use according to any of items    47 to 56, wherein a front edge (51) of the body (46) surrounding the    inhalation opening (42) is curved in a plan view and/or side view.-   58. The pharmaceutical composition for use according to any of items    47 to 57, wherein the inlet port (41) is conical to be    force-fittingly connectable to a boss (106) of the nebulizer (100).-   59. The pharmaceutical composition for use according to any of items    47 to 58, wherein the inhalation opening (42) is oval-shaped in a    front view, the oval shape having a minor axis and a major axis,    wherein the filter base (31) extends from the body (46) in a    direction along the minor axis.-   60. A method for preventing or treating a pulmonary disease or    condition in a subject, the method comprising the step of    administering an inhalable immunosuppressive macrocyclic active    ingredient to said subject by inhalation in form of an aerosol    comprising the immunosuppressive macrocyclic active ingredient,    -   wherein the aerosol is generated by nebulization of the        pharmaceutical composition using a nebulizer (100), the        nebulizer comprising:    -   a) an aerosol generator (101) comprising:        -   a fluid reservoir (103) or an interface configured to            connect a fluid reservoir, and        -   a vibratable membrane (110) having a plurality of apertures,            the apertures being adapted to produce an aerosol comprising            droplets having a mass median aerodynamic diameter (MMAD) of            up to about 4.0 μm as measured with a 0.9% (w/v) aqueous            solution of sodium chloride;    -   b) a chamber (105) for temporarily accommodating the aerosol        generated by the aerosol generator, the chamber having an inner        lumen with a volume in the range of from about 50 to about 150        ml; and    -   c) a mouthpiece (40) for delivering the aerosol supplied by the        nebulizer 100 to the subject, the mouthpiece having an        exhalation filter (30).-   61. The method according to item 60, further comprising the step of    -   providing a pharmaceutical composition comprising an inhalable        immunosuppressive macrocyclic active ingredient in form of an        aqueous liquid solution.-   62. The use of an inhalable immunosuppressive macrocyclic active    ingredient in the manufacture of a pharmaceutical composition for    the prevention or treatment of a pulmonary disease or condition in a    subject by inhalation, wherein the pharmaceutical composition is    administered to the subject by inhalation in form of an aerosol,    -   wherein the pharmaceutical composition is administered to the        subject by inhalation in form of an aerosol, and    -   wherein the aerosol is generated by nebulization of the        pharmaceutical composition using a nebulizer (100), the        nebulizer comprising:    -   a) an aerosol generator (101) comprising:        -   a fluid reservoir (103) for holding the pharmaceutical            composition or an interface configured to connect a fluid            reservoir, and        -   a vibratable membrane (110) having a plurality of apertures,            the apertures being adapted to produce an aerosol comprising            droplets having a mass median aerodynamic diameter (MMAD) of            up to about 4.0 μm as measured with a 0.9% (w/v) aqueous            solution of sodium chloride;    -   b) a chamber (105) for temporarily accommodating the aerosol        generated by the aerosol generator (101), the chamber having an        inner lumen with a volume in the range of from about 50 to about        150 ml; and    -   c) a mouthpiece (40) for delivering the aerosol supplied by the        nebulizer (100) to the subject, the mouthpiece having an        exhalation filter (30).-   63. A kit comprising    -   a pharmaceutical composition comprising an inhalable        immunosuppressive macrocyclic active ingredient for use in the        prevention or treatment of a pulmonary disease or condition in a        subject; and    -   a nebulizer (100), the nebulizer comprising:        -   a) an aerosol generator (101) comprising:            -   a fluid reservoir (103) for holding the pharmaceutical                composition or an interface configured to connect a                fluid reservoir, and            -   a vibratable membrane (110) having a plurality of                apertures, the apertures being adapted to produce an                aerosol comprising droplets having a mass median                aerodynamic diameter (MMAD) of up to about 4.0 μm as                measured with a 0.9% (w/v) aqueous solution of sodium                chloride;        -   b) a chamber (105) for temporarily accommodating the aerosol            generated by the aerosol generator (101), the chamber having            an inner lumen with a volume in the range of from about 50            to about 150 ml; and        -   c) a mouthpiece (40) for delivering the aerosol supplied by            the nebulizer (100) to the subject, the mouthpiece having an            exhalation filter (30).-   64. The kit according to item 63, wherein the pharmaceutical    composition comprising an inhalable immunosuppressive macrocyclic    active ingredient for use in the prevention or treatment of a    pulmonary disease or condition in a subject is provided in form of a    preformed liquid aqueous composition.-   65. The kit according to item 64, wherein the pharmaceutical    composition comprising an inhalable immunosuppressive macrocyclic    active ingredient for use in the prevention or treatment of a    pulmonary disease or condition in a subject is provided in form of a    lyophilisate comprising the inhalable immunosuppressive macrocyclic    active ingredient and a sterile liquid aqueous carrier liquid for    the reconstitution of the lyophilsate to form a liquid    pharmaceutical composition.

The following examples serve to illustrate the invention; however, theseare not to be understood as restricting the scope of the invention:

EXAMPLES Example 1

-   1.1 Step 1: Preparation of liposomal solution of cyclosporine A:-   1.1.1 Approximately 70% (-104 L) water for injections was filled    into the preparation vessel. It was degassed by introduction of    nitrogen gas and warmed up to a temperature of 40 to 45 ° C. 18.0 kg    of saccharose, 450.0 g of sodium dihydrogen phosphate dihydrate,    612.0 g of disodium hydrogen phosphate decahydrate and 36.0 g of    disodium edetate were added together and approximately 5% (8,0 L) of    water for injections were used for rinsing. The mixture was stirred    until a visually clear solution was obtained. The solution was    cooled down to 20 to 25 ° C. and 6480.0 g of soy bean lecithin S100    (Lipoid S100) was added and stirred until a homogenous dispersion    was obtained. Then, 504.0 g of polysorbate 80 HP (Tween 80) was    added under gentle stirring to avoid foaming and the container    holding the polysorbate was rinsed with approximately 100 mL of    water for injections. After that, 720.0 g of cyclosporine A and    approximately 5% (8 L) of water for injections was added and the    mixture was stirred until a homogenous dispersion was formed.-   1.1.2 Following that, the resulting dispersion was cooled to a    temperature of 5 to 10 ° C. and exposed to high pressure    homogenization at a pressure of 100 bar (first stage) and 1000 bar    (second stage), respectively, using a GEA high pressure homogenizer.    The high-pressure homogenization was repeated 9 times (cycles).-   1.1.3 The resulting homogenized suspension was then filtered through    a bioburden reduction filter with a pore size of 0.2 μm in minimum    once and transferred into a filling/storage tank.-   1.2 Step 2: Aseptic Filling, lyophilization and packaging-   1.2.1 Glass vials with a filling volume of 10 mL were sterilized in    a hot-air sterilizing tunnel, cooled down and filled with aliquots    of 1.35 mL (5mg dosage) of the dispersion as prepared according to    step 1 as described above after aseptic sterilisation using 2    sterile filters with a pore size of 0.2 μm between the    filling/storage tank and the filling needles. The vials were then    partially closed with sterilized lyophilization stoppers and loaded    into a lyophilizer, i.e. a GEA Lyovac FCM and were lyophilized    according to a 72 h lyophilization cycle.-   1.2.2 After completion of lyophilization, the vials were    automatically fully stoppered in the lyophilization chamber. The    vials were unloaded and closed with flip-tear-off caps. Each vial    contained approximately 190 mg of an almost white, homogenous,    porous lyophilization cake containing 5 mg of cyclosporine A in    liposomally solubilized form with a maximum residual moisture of 2%    (w/w) and a shelf life of 3 years.-   1.2.3 The composition of the lyophilized drug product prepared as    described above is summarized in Table 1 below:

TABLE 1 Quantity Quantity Ingredient per unit % (w/w) Cyclosporine A 5mg 2.69 Polysorbate 80 3.5 mg 1.88 Lipoid S100 45 mg 24.18 Sucrose 125mg 67.16 Sodium dihydrogen 3.125 mg 1.68 phosphate dihydrate Disodiumhydrogen 4.25 mg 2.28 phosphate dodecahydrate Disodium edetate 0.25 mg0.13 dihydrate Total 186.125 mg 100.00

Example 2 Reconstitution of the lyophilized composition comprisingcyclosporine A to yield a colloidal solution of liposomally solubilizedcyclosporine A for nebulization and inhalation

-   2.1 For the preparation of a colloidal solution with a content of    liposomally solubilized cyclosporine A of 10 mg, an aliquot of 372.3    mg of the lyophilization cake as prepared according to Example 1    above was dissolved in 2.65 mL of a sterile aqueous sodium chloride    solution with a concentration of 0.25% (w/v) to give an opalescent    aqueous solution of liposomal cyclosporine A for inhalation purposes    with a concentration of CsA of 4 mg/mL.-   2.2 The composition of the reconstituted drug product prepared as    described above is summarized in Table 2 below:

TABLE 2 Quantity Quantity Ingredient per unit % (w/v) Cyclosporine A 10mg 0.4 Polysorbate 80 7.5 mg 0.28 Lipoid S100 90 mg 3.6 Sucrose 250 mg10 Sodium dihydrogen 6.25 mg 0.25 phosphate dihydrate Disodium hydrogen8.5 mg 0.34 phosphate dodecahydrate Disodium edetate 0.5 mg 0.02dihydrate Sodium chloride 5.6 mg 0.22 or 0.23 Water for Injection Ad 2.5mL Ad 100

Example 3

-   3.1 The breath simulation experiments were conducted according to    Eur. Ph. 2.9.44 using a Compas 2 breath simulator (PARI GmbH,    Germany) with a breathing pattern of 500 mL tidal volume at a    frequency of 15 breaths/min and an inhalation/exhalation ratio of    50:50.-   3.2 2.4 mL of the composition as described in Example 2.2 above were    filled into an electronic vibrating membrane nebulizer having a    membrane adapted to produce an aerosol with particle having a mass    median aerodynamic diameter (MMAD) in the range of 2.4 to 4.0 μm    when measured with a 0.9% (w/v) solution of aqueous sodium chloride.    The nebulizer further had a mixing chamber with a volume of 94 mL.    The nebulizer was connected to a sinus pump of the breath simulator.    The drug containing aerosol droplets were collected on 2 consecutive    inspiratory filter (polypropylene filter pad G300, PARI, in filter    casing with a diameter of 6.5 cm). Between the inspiratory filter    and the breath simulator a further filter was installed (BB50 TE,    Pall Filtersystems GmbH, Germany).-   3.3 After complete nebulization, the inhalation filters were    removed, extracted and the extracts analyzed.-   3.4 The results of breath simulation experiments as described above    are summarized in Table 3 below:

TABLE 3 Mean Standard value deviation (SD) Total Output Rate (TOR)[mg/min] 245 31 Delivered Dose (DD) [mg] 6.916 0.322 Delivered Dose (DD)[%] 72.0 3.4 Exhaled amount [mg] 0.899 0.271 Exhaled amount [%] 9.4 2.8Residue in nebulizer [mg] 1.253 0.379 Residue in nebulizer [%] 13.1 4.0Respirable dose (RD ≤ 5 μm) [mg] 5.620 0.465 Respirable dose (RD ≤ 5 μm)[%] 58.5 4.8 End of aerosol production [min] 9.64 1.62 Automated shutoff[min] 9.98 1.58

Example 4

-   4.1 In addition to this, the generated aerosol was characterized    according to USP chapter <1601> resp. Ph. Eur. 2.9.44 using the Next    Generation Impactor (Next Generation Cascade Impactor, NGI) to    assess the aerodynamic droplet size distribution of the nebulized    aerosols at an airflow of 15.0+/−0.7 L/min, an air temperature of    23.0+/−2.0° C. and a relative humidity of 50.0+/−5.0%. The fill    volume was 2.4 mL of the composition as described in Example 2.2.    Deviating from the USP procedure the impactor temperature was    adapted to the aerosol temperature (18.0 +/−1.0° C.). The nebulizers    with the mouthpieces attached were connected via a rubber connector    to the induction port of the NGI. The nebulization was conducted and    operated until the automatic shutoff of the nebulizer.-   4.2 The results of the aerosol characterization experiments (n=5) as    described above are summarized in Table 4 below:

TABLE 4 Mean Standard value deviation (SD) Mass median aerodynamicdiameter (MMAD) 3.26 0.24 [μm] Geometric Standard Deviation (GSD) 1.620.04 Fine Particle Dose (FPD ≤ 5 μm) [mg] 6.951 0.475 Fine ParticleFraction (FPF ≤ 5 μm) [%] 81.2 4.7 End of aerosol production [min] 10.11.18 Automated shutoff [min] 10.41 1.25

Comparative Example 1

Examples 3 and 4 were repeated using an eFlow® Rapid electronicnebulizer (PARI GmbH, Germany) having a vibratable membrane adapted toproduce an aerosol with particle having a mass median aerodynamicdiameter of 4.1 μm when measured with a 0.9% (w/v) solution of aqueoussodium chloride. The nebulizer further had a mixing chamber with avolume of 48 mL. The results are summarized in Table 5 below:

TABLE 5 Mean Standard value deviation (SD) Total Output Rate (TOR)[mg/min] 192 17 Mass median aerodynamic diameter (MMAD) 3.25 0.15 [μm]Geometric Standard Deviation (GSD) 1.54 0.02 Fine Particle Fraction (FPF≤ 5 μm) [%] 86.7 2.2 Delivered Dose (DD) [mg] 3.649 0.253 Delivered Dose(DD) [%] 36.5 2.5 Exhaled amount [mg] 1.287 0.486 Exhaled amount [%]12.9 4.9 Residue in nebulizer [mg] 4.704 0.407 Residue in nebulizer [%]47.0 4.1 Respirable dose (RD ≤ 5 μm) [mg] 3.161 0.182 Respirable dose(RD ≤ 5 μm) [%] 31.6 1.8 End of aerosol production [min] 6.80 0.54Automated shutoff [min] 7.01 0.60

1-32. (canceled)
 33. A pharmaceutical composition comprisingcyclosporine A in liposomally solubilized form (L-CsA) for use in theprevention or treatment of a pulmonary disease or condition in asubject, wherein the pharmaceutical composition is administered to thesubject by inhalation in form of an aerosol, and wherein the aerosol isgenerated by nebulization of the pharmaceutical composition using anebulizer (100), the nebulizer comprising: a) an aerosol generator (101)comprising: a fluid reservoir (103) for holding the pharmaceuticalcomposition or an interface configured to connect a fluid reservoir, anda vibratable membrane (110) having a plurality of apertures, theapertures being adapted to produce an aerosol comprising droplets havinga mass median aerodynamic diameter (MMAD) of up to about 4.0 μm asmeasured with a 0.9% (w/v) aqueous solution of sodium chloride; b) achamber (105) for temporarily accommodating the aerosol generated by theaerosol generator (101), the chamber having an inner lumen with a volumein the range of from about 50 to about 150 ml; and c) a mouthpiece (40)for delivering the aerosol supplied by the nebulizer (100) to thesubject, the mouthpiece having an exhalation filter (30); wherein themouthpiece (40) comprises: a body (46) defining a fluid path (47) froman inlet port (41) connectable to the nebulizer (100) to an inhalationopening (42) to be received in the mouth of the user; and an exhalationfilter (30) having a filter base (31) in fluid communication with thefluid path (47), a filter top (33) detachably connected to the filterbase (31) and a filter material (32) provided between the filter base(31) and the filter top (33), wherein the filter top (33) has anexhalation opening (36) cooperating with a one-way valve (39) allowingexhaustion of fluid from the fluid path (47) through the filter material(32) to the outside of the mouthpiece (40) upon exhalation of a patientthrough the inhalation opening; wherein the body (46) and the filterbase (31) are an integrated one-piece unit.
 34. The pharmaceuticalcomposition for use according to claim 1, wherein the pulmonary diseaseor condition is selected from the group consisting of asthma, refractoryasthma, chronic obstructive bronchitis, parenchymal, fibrotic andinterstitial lung diseases and inflammations, bronchiolitis obliterans(BOS), and acute and chronic organ transplant rejection reactions afterlung transplantations and the diseases resulting therefrom.
 35. Thepharmaceutical composition for use according to claim 1, wherein thepulmonary disease or condition is bronchiolitis obliterans (BOS) grade Ior higher, specifically BOS grade I or II, especially BOS grade I. 36.The pharmaceutical composition for use according to claim 1, comprisingcyclosporine A in a concentration in the range of from about 1 mg/mL toabout 10 mg/mL.
 37. The pharmaceutical composition for use according toclaim 1, wherein the liquid aqueous composition comprises cyclosporine Ain liposomally solubilized form (L-CsA) in a concentration in the rangeof from about 3 mg/mL to about 5 mg/mL.
 38. The pharmaceuticalcomposition for use according to claim 1, wherein the composition is aliquid composition comprising an aqueous liquid vehicle.
 39. Thepharmaceutical composition for use according to claim 38, wherein theaqueous liquid composition comprising cyclosporine A in liposomallysolubilized form is obtained by reconstitution of a lyophilisatecomprising cyclosporine A and liposome forming structures.
 40. Thepharmaceutical composition for use according to claim 39, wherein theliposome-forming structures comprise a bilayer membrane formed of amembrane-forming substance selected from the group of phospholipids. 41.The pharmaceutical composition for use according to claim 40, whereinthe membrane-forming substance selected from the group of phospholipidsis a mixture of natural phospholipids.
 42. The pharmaceuticalcomposition for use according to claim 40, wherein the membrane-formingsubstance selected from the group of phospholipids is a lecithincontaining unsaturated fatty acid residues.
 43. The pharmaceuticalcomposition for use according to claim 40, wherein the membrane formingsubstance selected from the group of phospholipids is a lecithinselected from the group consisting of soy bean lecithin, Lipoid S75,Lipoid S100, Phospholipon® G90, 100 or a comparable lecithin.
 44. Thepharmaceutical composition for use according to claim 1, wherein thecomposition further comprises at least one solubility-enhancingsubstance selected from the group of non-ionic surfactants.
 45. Thepharmaceutical composition for use according to claim 44, wherein the atleast one non-ionic surfactant is selected from the group ofpolysorbates.
 46. The pharmaceutical composition for use according toclaim 44, wherein the solubility-enhancing substance selected from thegroup of non-ionic surfactants is polysorbate
 80. 47. The pharmaceuticalcomposition for use according to claim 45, wherein the weight ratio ofphospholipid to polysorbate is selected in the range of from about 15:1to about 9:1, preferably between from about 14:1 to about 12:1, forexample, about 13:1.
 48. The pharmaceutical composition for useaccording to claim 1, wherein the composition comprises at least onedisaccharide selected from the group consisting of saccharose, lactoseand trehalose, preferably saccharose.
 49. The pharmaceutical compositionfor use according to claim 48, wherein the composition comprises atleast one disaccharide selected from the group consisting of saccharose,lactose and trehalose, preferably saccharose, in the range of from about5 to about 15 wt.-%, preferably in the range of from about 7.5 to about12.5 wt.-%, based on the total weight of the pharmaceutical composition.50. The pharmaceutical composition for use according to claim 40,wherein the cyclosporine A is at least partially incorporated (orintercalated) in the bilayer membrane of the liposome-formingstructures.
 51. The pharmaceutical composition for use according toclaim 1, wherein the vibratable membrane (110) has from about 100 toabout 400 apertures per mm².
 52. The pharmaceutical composition for useaccording to claim 1, wherein the plurality of apertures of thevibratable membrane (110) have a tapered shape narrowing towards theaerosol release side of the vibratable membrane.
 53. The pharmaceuticalcomposition for use according to claim 1, wherein the apertures of thevibratable membrane have an exit diameter in the range of from about 1.5μm to about 3.0 μm as measured by scanning electron microscopy (SEM).54. The pharmaceutical composition for use according to claim 1, whereinthe inhalable immunosuppressive macrocyclic active ingredient isdelivered to the lungs (or the lung) of the subject in an amount(Delivered dose, DD) of at least 70%, more specifically in an amount inthe range of from about 70% to about 80% of the amount administered tothe subject.
 55. The pharmaceutical composition for use according toclaim 1, wherein the aerosol administered to the patient comprisesdroplets and wherein from about 60% to about 95% of the total number ofdroplets have a diameter of up to 5 μm (as measured by laser diffractionor by a multistage cascade impactor as described above) when measuredwith a aqueous composition comprising L-CsA in a concentration of 4mg/mL.
 56. The pharmaceutical composition for use according to claim 1,wherein the inhalable immunosuppressive macrocyclic active ingredient isadministered to the subject at a total output rate (TOR) of at least 200mg/min, more specifically at a total output rate in the range of fromabout 200 to about 250 mg/min.
 57. The pharmaceutical composition foruse according to claim 1, wherein the amount of the inhalableimmunosuppressive macrocyclic active ingredient exhaled by the subjectis up to 10%, more specifically from about 4% to about 8% of the totalamount of active ingredient administered to the subject.
 58. Thepharmaceutical composition for use according to claim 1, wherein 1 mL ofthe pharmaceutical composition comprising an inhalable immunosuppressivemacrocyclic active ingredient is aerosolized (nebulized) within a periodof up to about 5 min.
 59. A kit comprising a pharmaceutical compositioncomprising cyclosporine A in liposomally solubilized form for use in theprevention or treatment of a pulmonary disease or condition in asubject; and a nebulizer (100), the nebulizer comprising: a) an aerosolgenerator (101) comprising: a fluid reservoir (103) for holding thepharmaceutical composition or an interface configured to connect a fluidreservoir, and a vibratable membrane (110) having a plurality ofapertures, the apertures being adapted to produce an aerosol comprisingdroplets having a mass median aerodynamic diameter (MMAD) of up to about4.0 μm as measured with a 0.9% (w/v) aqueous solution of sodiumchloride; b) a chamber (105) for temporarily accommodating the aerosolgenerated by the aerosol generator (101), the chamber having an innerlumen with a volume in the range of from about 50 to about 150 ml; andc) a mouthpiece (40) for delivering the aerosol supplied by thenebulizer (100) to the subject, the mouthpiece having an exhalationfilter (30) wherein the mouthpiece (40) comprises: a body (46) defininga fluid path (47) from an inlet port (41) connectable to the nebulizer(100) to an inhalation opening (42) to be received in the mouth of theuser; and an exhalation filter (30) having a filter base (31) in fluidcommunication with the fluid path (47), a filter top (33) detachablyconnected to the filter base (31) and a filter material (32) providedbetween the filter base (31) and the filter top (33), wherein the filtertop (33) has an exhalation opening (36) cooperating with a one-way valve(39) allowing exhaustion of fluid from the fluid path (47) through thefilter material (32) to the outside of the mouthpiece (40) uponexhalation of a patient through the inhalation opening; wherein the body(46) and the filter base (31) are an integrated one-piece unit.
 60. Thekit according to claim 59, wherein the pharmaceutical compositioncomprising cyclosporine A in liposomally solubilized form for use in theprevention or treatment of a pulmonary disease or condition in a subjectis provided in form of a preformed liquid aqueous composition.
 61. Thekit according to claim 60, wherein the pharmaceutical compositioncomprising cyclosporine A in liposomally solubilized form for use in theprevention or treatment of a pulmonary disease or condition in a subjectis provided in form of a lyophilisate comprising the inhalableimmunosuppressive macrocyclic active ingredient and a sterile liquidaqueous carrier liquid for the reconstitution of the lyophilsate to forma liquid pharmaceutical composition.